MH_dev_110

The stimulation of ketogenesis by cannabinoids in cultured astrocytes defines carnitine palmitoyltransferase I as a new ceramide-activated enzyme . The effects of cannabinoids on ketogenesis in primary cultures of rat astrocytes were studied . Delta 9 - DB00470 SUB ( THC ) , the major active component of marijuana , produced a malonyl - DB01992 - independent stimulation of carnitine palmitoyltransferase I ( CPT-I ) and ketogenesis from [ 14C ] palmitate . The THC-induced stimulation of ketogenesis was mimicked by the synthetic cannabinoid HU - 210 and was prevented by pertussis toxin and the P21554 REA cannabinoid receptor antagonist SR141716 . Experiments performed with different cellular modulators indicated that the THC-induced stimulation of ketogenesis was independent of cyclic AMP , Ca2 + , protein kinase C , and mitogen-activated protein kinase ( MAPK ) . The possible involvement of ceramide in the activation of ketogenesis by cannabinoids was subsequently studied . THC produced a P21554 REA receptor-dependent stimulation of sphingomyelin breakdown that was concomitant to an elevation of intracellular ceramide levels . Addition of exogenous sphingomyelinase to the astrocyte culture medium led to a MAPK-independent activation of ketogenesis that was quantitatively similar and not additive to that exerted by THC . Furthermore , ceramide activated CPT-I in astrocyte mitochondria . Results thus indicate that cannabinoids stimulate ketogenesis in astrocytes by a mechanism that may rely on P21554 REA receptor activation , sphingomyelin hydrolysis , and ceramide-mediated activation of CPT-I .

Depolarization-induced suppression of excitation in murine autaptic hippocampal neurones . Depolarization-induced suppression of excitation and inhibition ( Q9UL01 and DSI ) appear to be important forms of short-term retrograde neuronal plasticity involving endocannabinoids ( eCB ) and the activation of presynaptic cannabinoid P21554 REA receptors . We report here that P21554 REA - dependent Q9UL01 can be elicited from autaptic cultures of excitatory mouse hippocampal neurones . Q9UL01 in autaptic cultures is both more robust and elicited with a more physiologically relevant stimulus than has been thus far reported for conventional hippocampal cultures . An additional requirement for autaptic Q9UL01 is filled internal calcium stores . Pharmacological experiments favour a role for 2 - arachidonyl glycerol ( 2 - AG ) rather than arachidonyl ethanolamide ( AEA ) or noladin ether as the relevant endocannabinoid to elicit Q9UL01 . In particular , the latter two compounds fail to reversibly inhibit EPSCs , a quality inconsistent with the role of bona fide eCB mediating Q9UL01 . Delta 9 - DB00470 SUB ( delta 9 - THC ) fails to inhibit EPSCs , yet readily occludes both Q9UL01 and EPSC inhibition by a synthetic P21554 REA agonist , Q08050 REA 55212-2 . With long-term exposure ( approximately 18 h ) , delta 9 - THC also desensitizes P21554 REA receptors . Lastly , a functional endocannabinoid transporter is necessary for the expression of Q9UL01 .

No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( DB00422 MENMAX DB00422 MEN ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 REA , P28222 REA , Q8IWU9 , P09172 REA , P21917 REA , P21964 REA , and P60880 REA ) in the response to DB00422 MEN in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between DB00422 MEN responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of DB00422 MEN among adults with ADHD .

AB-CHMINACA , AB-PINACA , and FUBIMINA : Affinity and Potency of Novel Synthetic Cannabinoids in Producing Δ9 - DB00470 SUB - Like Effects in Mice . Diversion of synthetic cannabinoids for abuse began in the early 2000s . Despite legislation banning compounds currently on the drug market , illicit manufacturers continue to release new compounds for recreational use . This study examined new synthetic cannabinoids , AB-CHMINACA ( N - [ 1 - amino - 3 - methyl-oxobutan - 2 - yl ] - 1 - [ cyclohexylmethyl ] - 1H - indazole - 3 - carboxamide ) , AB-PINACA [ N - ( 1 - amino - 3 - methyl - 1 - oxobutan - 2 - yl ) - 1 - pentyl - 1H - indazole - 3 - carboxamide ] , and FUBIMINA [ ( 1 - ( 5 - fluoropentyl ) - 1H - benzo [ d ] imadazol - 2 - yl ) ( naphthalen - 1 - yl ) methanone ] , with the hypothesis that these compounds , like those before them , would be highly susceptible to abuse . Cannabinoids were examined in vitro for binding and activation of P21554 REA receptors , and in vivo for pharmacological effects in mice and in Δ ( 9 ) - tetrahydrocannabinol ( Δ ( 9 ) - THC ) discrimination . AB-CHMINACA , AB-PINACA , and FUBIMINA bound to and activated P21554 REA and CB2 receptors , and produced locomotor suppression , antinociception , hypothermia , and catalepsy . Furthermore , these compounds , along with JWH - 018 [ 1 - pentyl - 3 - ( 1 - naphthoyl ) indole ] , Q13515 , 497 [ rel - 5 - ( 1,1- dimethylheptyl ) - 2 - [ ( 1R , 3S ) - 3 - hydroxycyclohexyl ] - phenol ] , and WIN 55,212- 2 ( [ ( 3R ) -2,3- dihydro - 5 - methyl - 3 - ( 4 - morpholinylmethyl ) pyrrolo [ 1,2 , 3 - de ] -1,4- benzoxazin - 6 - yl ] - 1 - naphthalenyl-methanone , monomethanesulfonate ) , substituted for Δ ( 9 ) - THC in Δ ( 9 ) - THC discrimination . Rank order of potency correlated with P21554 REA receptor-binding affinity , and all three compounds were full agonists in [ ( 35 ) S ] GTPγS binding , as compared with the partial agonist Δ ( 9 ) - THC . Indeed , AB-CHMINACA and AB-PINACA exhibited higher efficacy than most known full agonists of the P21554 REA receptor . Preliminary analysis of urinary metabolites of the compounds revealed the expected hydroxylation . AB-PINACA and AB-CHMINACA are of potential interest as research tools due to their unique chemical structures and high P21554 REA receptor efficacies . Further studies on these chemicals are likely to include research on understanding cannabinoid receptors and other components of the endocannabinoid system that underlie the abuse of synthetic cannabinoids .

Post - DB00669 era for the treatment of acute migraine . There now is one realized and several attractive targets for the treatment of acute attacks of migraine that will follow and augment the use of serotonin P28222 REA / 1D receptor agonists , the triptans . P01258 REA gene-related peptide ( P8 0511 ) receptor blockade recently has been shown to be an effective acute antimigraine strategy ; therefore , blockade of P8 0511 release by inhibition of trigeminal nerves would seem a logical approach . A number of targets are reviewed in this article including serotonin P30939 REA and P28221 REA receptors , adenosine A1 receptors , nociceptin , vanilloid Q8NER1 receptors , and anandamide P21554 REA receptors . Development of one or more such compound offers the exciting prospect of new non-vasoconstrictor treatments for migraine and cluster headache .

Vascular effects of delta 9 - tetrahydrocannabinol ( THC ) , anandamide and N-arachidonoyldopamine ( NADA ) in the rat isolated aorta . The vascular effects of cannabinoids have been compared in the rat isolated aorta . Delta 9 - DB00470 SUB ( THC ) , anandamide and N-arachidonoyl-dopamine ( NADA ) all caused vasorelaxation to similar degrees in pre-constricted aortae . Vasorelaxation to THC was inhibited by in vivo pre-treatment with pertussis toxin ( 10 microg / kg ) or with the synthetic cannabinoid CP55 , 940 ( ( ( - ) - cis - 3 - [ 2 - hydroxy - 4 - ( 1,1- dimethylheptyl ) phenyl ] - trans - 4 - ( 3 - hydroxypropyl ) cyclohexanol ) , acutely or chronically ) , exposure to capsaicin in vitro ( 10 microM for 1 h ) , and de-endothelialisation . Vasorelaxation to anandamide was only inhibited by pertussis toxin and chronic CP55 , 940 pre-treatment ( 0.4 mg / kg for 11 days ) . Vasorelaxation to NADA was inhibited by pertussis toxin and chronic CP55 , 940 pre-treatment , and by de-endothelialisation . The vasorelaxant effects of the cannabinoids were not inhibited by cannabinoid P21554 REA receptor antagonism ; however , vasorelaxation to both CP55 , 940 and THC was inhibited by cannabinoid CB2 receptor antagonism . Vasorelaxation to all cannabinoids was enhanced in the presence of indomethacin ( 10 microM ) . THC also caused vasoconstriction of the aorta while anandamide , NADA , CP55 , 940 and Q08050 REA 55,212- 2 ( R ( + ) - [ 2,3- dihydro - 5 - methyl - 3 - [ ( morpholinyl ) methyl ] pyrrolo [ 1,2 , 3 - de ] -1,4 benzoxazin-yl ] - ( 1 - naphthalenyl ) methanone mesylate ) did not . The vasoconstrictor effects of THC were inhibited by in vivo pre-treatment with pertussis toxin or CP55 , 940 , acute exposure to CP55 , 940 , cannabinoid P21554 REA receptor antagonism and cyclooxygenase inhibition . These results demonstrate the opposing vascular effects of cannabinoids in the rat aorta , and although vasorelaxation to each of the cannabinoids is of similar magnitude , it is mediated through different pathways . This gives further indication of the different vascular actions of cannabinoid compounds .

Attenuation of inducible nitric oxide synthase gene expression by delta 9 - tetrahydrocannabinol is mediated through the inhibition of nuclear factor - kappa B / Rel activation . delta 9 - DB00470 SUB ( delta 9 - THC ) a prototypic compound belonging to the family of agents known as cannabinoids , produces a wide variety of biological effects , including inhibition of immune function . The putative mechanism for cannabinoid biological action involves binding to cannabinoid receptor types 1 and 2 ( P21554 REA and CB2 ) to negatively regulate adenylate cyclase and inhibit intracellular signaling via the DB02527 cascade . In the current study , we show that delta 9 - THC produces a marked inhibition of inducible nitric oxide synthase ( P35228 REA ) transcription and nitric oxide production by the macrophage line RAW 264.7 in response to lipopolysaccharide ( LPS ) . Analysis of RAW 264.7 cell RNA demonstrated transcripts for CB2 but not P21554 REA . Treatment of RAW 264.7 with delta 9 - THC inhibited forskolin-stimulated DB02527 production in a dose-related manner , verifying the expression of functional cannabinoid receptors by this cell line . P35228 REA transcription , which is regulated in part by the nuclear factor-kappa B / Rel ( NF-kappa B / Rel ) family of transcription factors , has been shown to be under the control of the DB02527 signaling cascade . We demonstrate that delta 9 - THC inhibits the activation and binding of NF-kappa B / Rel proteins to their cognate DNA site , kappa B , in response to LPS stimulation . LPS treatment of RAW 264.7 cells also induced the activation of the DB02527 cascade , as indicated by an increase in binding of nuclear factors to the DB02527 response element . Activation of CRE binding proteins was inhibited by delta 9 - THC . DB02587 treatment of RAW 264.7 cells induced both kappa B and DB02527 response element binding activity and was likewise inhibited by delta 9 - THC . Collectively , this series of experiments indicates that NF-kappa B / Rel is positively regulated by the DB02527 cascade to help initiate P35228 REA gene expression in response to LPS stimulation of macrophages . This activation of P35228 REA is attenuated by delta 9 - THC through the inhibition of DB02527 signaling .

Anti-inflammatory activity of topical THC in DNFB-mediated mouse allergic contact dermatitis independent of P21554 REA and CB2 receptors . BACKGROUND : ∆ ( 9 ) - DB00470 SUB ( THC ) , the active constituent of Cannabis sativa , exerts its biological effects in part through the G-protein-coupled P21554 REA and CB2 receptors , which were initially discovered in brain and spleen tissue , respectively . However , THC also has P21554 REA / 2 receptor-independent effects . Because of its immune-inhibitory potential , THC and related cannabinoids are being considered for the treatment of inflammatory skin diseases . Here we investigated the mechanism of the anti-inflammatory activity of THC and the role of P21554 REA and CB2 receptors . METHODS : We evaluated the impact of topically applied THC on DNFB-mediated allergic contact dermatitis in wild-type and P21554 REA / 2 receptor-deficient mice . We performed immunohistochemical analyses for infiltrating immune cells and studied the influence of THC on the interaction between T cells , keratinocytes and myeloid immune cells in vitro . RESULTS : Topical THC application effectively decreased contact allergic ear swelling and myeloid immune cell infiltration not only in wild-type but also in P21554 REA / 2 receptor-deficient mice . We found that THC ( 1 ) inhibited the production of IFNγ by T cells , ( 2 ) decreased the production of P13500 REA and of IFNγ-induced P8 0075 and CXL 10 by epidermal keratinocytes and ( 3 ) thereby limited the recruitment of myeloid immune cells in vitro in a P21554 REA / 2 receptor-independent manner . CONCLUSIONS : Topically applied THC can effectively attenuate contact allergic inflammation by decreasing keratinocyte-derived pro-inflammatory mediators that orchestrate myeloid immune cell infiltration independent of P21554 REA / 2 receptors . This has important implications for the future development of strategies to harness cannabinoids for the treatment of inflammatory skin diseases .

delta ( 9 ) - DB00470 SUB increases nerve growth factor production by prostate PC - 3 cells . Involvement of P21554 REA cannabinoid receptor and P04049 REA . Cannabinoids , the active components of marihuana , exert a variety of effects in humans . Many of these effects are mediated by binding to two types of cannabinoid receptor , P21554 REA and CB2 . Although P21554 REA is located mainly in the central nervous system , it may also be found in peripheral tissues . Here , we study the effect of cannabinoids in the production of nerve growth factor by the prostate tumor cell line PC - 3 . We show that addition of Delta ( 9 ) - tetrahydrocannabinol to PC - 3 cells stimulated nerve growth factor production in a dose-dependent and time-dependent manner . Maximal effect was observed at 0.1 microM Delta ( 9 ) - tetrahydrocannabinol and 72 h of treatment . Stimulation was reversed by the P21554 REA antagonists AM 251 and SR 1411716 A . Pre-treatment of cells with pertussis toxin also prevented the effect promoted by Delta ( 9 ) - tetrahydrocannabinol . These results indicate that Delta ( 9 ) - tetrahydrocannabinol stimulation of nerve growth factor production in these cells was mediated by the cannabinoid P21554 REA receptor . The implication of P04049 REA activation in the mode of action of Delta ( 9 ) - tetrahydrocannabinol is also suggested .

delta 9 - DB00470 SUB increases activity of tyrosine hydroxylase in cultured fetal mesencephalic neurons . The exposure of pregnant rats to delta 9 - tetrahydrocannabinol ( delta 9 - THC ) , the main psychoactive constituent of Cannabis sativa , during gestation and lactation , affects the gene expression and the activity of tyrosine hydroxylase ( TH ) in the brain of their offspring , measured at fetal and early postnatal ages , when the expression of this enzyme plays an important role in neural development . In the present article , we have examined whether delta 9 - THC is able to affect TH activity in cultured mesencephalic neurons obtained from fetuses at gestational d 14 . Thus , TH activity increased approximately twofold in cells obtained from naive fetuses when exposed for 24 h to medium containing delta 9 - THC . In addition , TH activity was also approx twofold higher in cells obtained from fetuses exposed daily to delta 9 - THC from d 5 of gestation than in cells obtained from control fetuses , when both were exposed to basal media . This effect of delta 9 - THC on TH activity seems to be produced via the activation to cannabinoid receptors , in particular the P21554 REA subtype , which would presumably be located in these cells . This is because the exposure to medium containing both delta 9 - THC and SR141716A , a specific antagonist for P21554 REA receptors , abolished the effect observed with delta 9 - THC alone . SR141716A alone was without effect on TH activity . Collectively , our results support the notion that delta 9 - THC increased TH activity in cultured mesencephalic neurons , as previously observed in vivo , and that this effect was produced by activation of P21554 REA receptors , which seem to be operative at these early ages . All this points to a role for the endogenous cannabimimetic system in brain development .

Role of endogenous cannabinoids in synaptic signaling . Research of cannabinoid actions was boosted in the 1990s by remarkable discoveries including identification of endogenous compounds with cannabimimetic activity ( endocannabinoids ) and the cloning of their molecular targets , the P21554 REA and CB2 receptors . Although the existence of an endogenous cannabinoid signaling system has been established for a decade , its physiological roles have just begun to unfold . In addition , the behavioral effects of exogenous cannabinoids such as DB00470 SUB , the major active compound of hashish and marijuana , await explanation at the cellular and network levels . Recent physiological , pharmacological , and high-resolution anatomical studies provided evidence that the major physiological effect of cannabinoids is the regulation of neurotransmitter release via activation of presynaptic P21554 REA receptors located on distinct types of axon terminals throughout the brain . Subsequent discoveries shed light on the functional consequences of this localization by demonstrating the involvement of endocannabinoids in retrograde signaling at GABAergic and glutamatergic synapses . In this review , we aim to synthesize recent progress in our understanding of the physiological roles of endocannabinoids in the brain . First , the synthetic pathways of endocannabinoids are discussed , along with the putative mechanisms of their release , uptake , and degradation . The fine-grain anatomical distribution of the neuronal cannabinoid receptor P21554 REA is described in most brain areas , emphasizing its general presynaptic localization and role in controlling neurotransmitter release . Finally , the possible functions of endocannabinoids as retrograde synaptic signal molecules are discussed in relation to synaptic plasticity and network activity patterns .

Potential antipsychotic properties of central cannabinoid ( P21554 REA ) receptor antagonists . Delta ( 9 ) - DB00470 SUB ( Delta ( 9 ) - THC ) , the principal psychoactive constituent of the Cannabis sativa plant , and other agonists at the central cannabinoid ( CB ( 1 ) ) receptor may induce characteristic psychomotor effects , psychotic reactions and cognitive impairment resembling schizophrenia . These effects of Delta ( 9 ) - THC can be reduced in animal and human models of psychopathology by two exogenous cannabinoids , cannabidiol ( DB09061 ) and SR141716 . DB09061 is the second most abundant constituent of Cannabis sativa that has weak partial antagonistic properties at the CB ( 1 ) receptor . DB09061 inhibits the reuptake and hydrolysis of anandamide , the most important endogenous CB ( 1 ) receptor agonist , and exhibits neuroprotective antioxidant activity . SR141716 is a potent and selective CB ( 1 ) receptor antagonist . Since both DB09061 and SR141716 can reverse many of the biochemical , physiological and behavioural effects of CB ( 1 ) receptor agonists , it has been proposed that both DB09061 and SR141716 have antipsychotic properties . Various experimental studies in animals , healthy human volunteers , and schizophrenic patients support this notion . Moreover , recent studies suggest that cannabinoids such as DB09061 and SR141716 have a pharmacological profile similar to that of atypical antipsychotic drugs . In this review , both preclinical and clinical studies investigating the potential antipsychotic effects of both DB09061 and SR141716 are presented together with the possible underlying mechanisms of action .

Gender-dependent behavioral and biochemical effects of adolescent DB00470 SUB in adult maternally deprived rats . Preclinical data support the long-term adverse effects on cognition , emotionality , and psychotic-like behaviors of adolescent exposure to natural and synthetic cannabinoids . To investigate whether the long-lasting adverse effects induced by cannabinoids in adolescence are influenced by early-life stress , female and male rats were subjected to 24 - h maternal deprivation at postnatal day ( P01160 REA ) 9 and treated with tetrahydrocannabinol ( THC ) during adolescence ( P01160 REA 35-45 ) according to our previously reported protocol . At adulthood , rats were tested in the novel object recognition , social interaction , and forced swim tests , to evaluate possible alterations in recognition memory , social behavior , and coping strategy . Moreover , cannabinoid P21554 REA receptor density and functionality , as well as DB01221 and dopamine D1 and D2 receptor densities were measured through autoradiographic binding studies . In female maternally deprived rats , THC failed to impair recognition memory , counteracted aggressiveness induced by maternal deprivation , whereas no interaction was observed in the passive coping behavior . In males , the association of the two events increased passive coping response without affecting other behaviors . This behavioral picture was accompanied by gender-dependent and region-specific alterations in DB01221 , D1 and D2 receptors . In conclusion , this study demonstrates that adolescent THC exposure might have different behavioral outcomes in animals previously exposed to early-life stress compared with non-stressed controls . The interaction between the two events is not univocal , and different combinations may arise depending on the sex of the animals and the behavior considered . Alterations in DB01221 , D1 and D2 receptors might be involved in the behavioral responses induced by maternal deprivation and in their modulation by THC .

Observation of an unusual electronically distorted semiquinone radical of P11498 REA metabolites in the active site of prostaglandin H synthase - 2 . The activation of the metabolites of airborne polychlorinated biphenyls ( PCBs ) into highly reactive radicals is of fundamental importance . We found that human recombinant prostaglandin H synthase - 2 ( hPGHS - 2 ) biotransforms dihydroxy-PCBs , such as 4 - chlorobiphenyl - 2 ' , 5 ' - hydroquinone ( 4 - P34972 REA ' , 5 ' - H ( 2 ) Q ) , into semiquinone radicals via one-electron oxidation . Using electron paramagnetic resonance ( EPR ) spectroscopy , we observed the formation of the symmetric quartet spectrum ( 1:3 : 3:1 by area ) of 4 - chlorobiphenyl - 2 ' , 5 ' - semiquinone radical ( 4 - P34972 REA ' , 5 ' - SQ ( ) ( - ) ) from 4 - P34972 REA ' , 5 ' - H ( 2 ) Q . This spectrum changed to an asymmetric spectrum with time : the change can be explained as the overlap of two different semiquinone radical species . Hindered rotation of the 4 - P34972 REA ' , 5 ' - SQ ( ) ( - ) appears not to be a major factor for the change in lineshape because increasing the viscosity of the medium with glycerol produced no significant change in lineshape . Introduction of a fluorine , which increases the steric hindrance for rotation of the dihydroxy - P11498 REA studied , also produced no significant changes . An in silico molecular docking model of 4 - P34972 REA ' , 5 ' - H ( 2 ) Q in the peroxidase site of hPGHS - 2 together with ab initio quantum mechanical studies indicate that the close proximity of a negatively charged carboxylic acid in the peroxidase active site may be responsible for the observed perturbation in the spectrum . This study provides new insights into the formation of semiquinones from P11498 REA metabolites and underscores the potential role of P35354 REA in the metabolic activation of PCBs .

The P28335 REA receptor agonist lorcaserin reduces nicotine self-administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . DB04871 MEN ( ( 1R ) - 8 - chloro - 1 - methyl -2,3 , 4,5- tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase-III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0.3- 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . DB04871 MEN ( 0.6- 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self-administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . DB04871 MEN also reduced the reinstatement of nicotine-seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . DB04871 MEN did not reinstate nicotine-seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0.3- 1 mg / kg ) reduced nicotine-induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five-choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine-motivated behaviors , and nicotine-induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .

Gating properties of Q14524 REA mutations and the response to mexiletine in long-QT syndrome type 3 patients . BACKGROUND : DB00379 MEN ( Mex ) has been proposed as a gene-specific therapy for patients with long-QT syndrome type 3 ( LQT 3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 REA ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT 3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 REA mutations in 5 symptomatic LQT 3 patients with different responses to Mex ( 6 to 8 mg . kg ( - 1 ) . d ( - 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; > /= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na ( + ) current from P29320 REA 293 cells transfected with wild-type ( WT ) or mutant Nav 1.5 . All mutations showed impaired inactivation of Na ( + ) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1/2 ) of steady-state inactivation . Furthermore , Mex produced use-dependent block with the order R1626P =P 1332L > S941N = WT > M1652R , suggesting that Mex-sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1/2 ) of steady-state inactivation correlate with the clinical response observed in LQT 3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT 3 .

Pharmacogenetics of antipsychotic-induced weight gain : review and clinical implications . Second-generation antipsychotics ( SGAs ) , such as risperidone , clozapine and olanzapine , are the most common drug treatments for schizophrenia . SGAs presented an advantage over first-generation antipsychotics ( FGAs ) , particularly regarding avoidance of extrapyramidal symptoms . However , most SGAs , and to a lesser degree FGAs , are linked to substantial weight gain . This substantial weight gain is a leading factor in patient non-compliance and poses significant risk of diabetes , lipid abnormalities ( that is , metabolic syndrome ) and cardiovascular events including sudden death . The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic-induced weight gain ( AIWG ) . We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases . There has been considerable progress reaffirming previous findings and discovery of novel genetic factors . The P28335 REA and leptin genes are among the most promising , and new evidence suggests that the P14416 REA , P01375 REA , P60880 REA and P32245 REA genes are also prominent risk factors . Further promising findings have been reported in novel susceptibility genes , such as P21554 REA , P08183 REA , ADRA 1A and Q9Y5U4 REA . More research is required before genetically informed , personalized medicine can be applied to antipsychotic treatment ; nevertheless , inroads have been made towards assessing genetic liability and plausible clinical application .

[ 18F ] MK - 9470 PET measurement of cannabinoid P21554 REA receptor availability in chronic cannabis users . Δ ( 9 ) - DB00470 SUB , the main psychoactive component of cannabis , exerts its central effects through activation of the cerebral type 1 cannabinoid ( P21554 REA ) receptor . Pre-clinical studies have provided evidence that chronic cannabis exposure is linked to decreased P21554 REA receptor expression and this is thought to be a component underlying drug tolerance and dependence . In this study , we make first use of the selective high-affinity positron emission tomography ( PET ) ligand [ ( 18 ) F ] MK - 9470 to obtain in vivo measurements of cerebral P21554 REA receptor availability in 10 chronic cannabis users ( age = 26.0 ± 4.1 years ) . Each patient underwent [ ( 18 ) F ] MK - 9470 PET within the first week following the last cannabis consumption . A population of 10 age-matched healthy subjects ( age = 23.0 ± 2.9 years ) was used as control group . Parametric modified standardized uptake value images , reflecting P21554 REA receptor availability , were calculated . Statistical parametric mapping and volume-of-interest ( VOI ) analyses of P21554 REA receptor availability were performed . Compared with controls , cannabis users showed a global decrease in P21554 REA receptor availability ( -11.7 percent ) . VOI-based analysis demonstrated that the P21554 REA receptor decrease was significant in the temporal lobe ( -12.7 percent ) , anterior ( -12.6 percent ) and posterior cingulate cortex ( -13.5 percent ) and nucleus accumbens ( -11.2 percent ) . Voxel-based analysis confirmed this decrease and regional pattern in P21554 REA receptor availability in cannabis users . These findings revealed that chronic cannabis use may alter specific regional P21554 REA receptor expression through neuroadaptive changes in P21554 REA receptor availability , opening the way for the examination of specific P21554 REA - cannabis addiction interactions which may predict future cannabis-related treatment outcome .

Cannabinoids against pain . Efficacy and strategies to reduce psychoactivity : a clinical perspective . The clinical use of cannabinoids is currently a topic of interest not exclusively , but most importantly , concerning different areas of pain therapy . One of the major obstacles in developing clinically acceptable compounds is the cannabimimetic side-effect profile of DB00470 SUB ( THC ) and other cannabinoids . This article gives a brief overview of the endocannabinoid system , its components and functions and explains the current approaches to avoiding cannabimimetic side effects by separating them from the therapeutic effects . One of these approaches is the addition of cannabidiol ( DB09061 ) as well as the use of preparations suitable for oromucosal application . Also cannabinoids , which primarily stimulate peripheral cannabinoid - 1 ( P21554 REA ) receptors or selectively cannabinoid - 2 ( CB2 ) receptors , can further separate analgesic activity from cannabimimetic activity . Local or topical modes of application are another attempt aiming in the same direction . Modulating the endogenous cannabinoid tone ( via the inhibition of endocannabinoid-metabolising enzymes ) is another strategy . The combination of THC in low , non-psychoactive doses with opioids has a synergistic effect and reduces opioid tolerance effects . Available data from these approaches are summarised and their more and less promising aspects are discussed .

Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease . In the current study , we examined whether ligation of CB2 receptors would lead to induction of apoptosis in tumors of immune origin and whether CB2 agonist could be used to treat such cancers . Exposure of murine tumors EL - 4 , LSA , and P8 15 to DB00470 SUB ( THC ) in vitro led to a significant reduction in cell viability and an increase in apoptosis . Exposure of EL - 4 tumor cells to the synthetic cannabinoid HU - 210 and the endogenous cannabinoid anandamide led to significant induction of apoptosis , whereas exposure to WIN 55212 was not effective . Treatment of EL - 4 tumor-bearing mice with THC in vivo led to a significant reduction in tumor load , increase in tumor-cell apoptosis , and increase in survival of tumor-bearing mice . Examination of a number of human leukemia and lymphoma cell lines , including Jurkat , Molt - 4 , and Sup-T 1 , revealed that they expressed CB2 receptors but not P21554 REA . These human tumor cells were also susceptible to apoptosis induced by THC , HU - 210 , anandamide , and the CB2 - selective agonist JWH - 015 . This effect was mediated at least in part through the CB2 receptors because pretreatment with the CB2 antagonist SR144528 partially reversed the THC-induced apoptosis . Culture of primary acute lymphoblastic leukemia cells with THC in vitro reduced cell viability and induced apoptosis . Together , the current data demonstrate that CB2 cannabinoid receptors expressed on malignancies of the immune system may serve as potential targets for the induction of apoptosis . Also , because CB2 agonists lack psychotropic effects , they may serve as novel anticancer agents to selectively target and kill tumors of immune origin .

Positive interaction between lapatinib and capecitabine in human breast cancer models : study of molecular determinants . The combination of lapatinib and capecitabine is approved in Her 2 + metastatic breast cancer . However , the pharmacological mechanisms for this association have not been fully elucidated . In this non-clinical study , we evaluated the efficacy of this association on a panel of six human breast cancer cell lines as a means to identify the molecular determinants of response to this combination . Cell viability was evaluated after concomitant / sequential exposure , and response / resistance determinants for each drug such as dihydropyrimidine dehydrogenase ( Q12882 REA ) , thymidylate synthase ( TS ) , thymidine phosphorylase , Bax , Bcl 2 , P21 levels , and phospho Q8NFH3 / 44 and P00533 REA / 2 signaling pathway were studied . DB01259 MEN proved to markedly downregulate TS activity , thus suggesting a subsequent better efficacy of capecitabine . DB01101 optimized the downregulation of p-AKT and p-P 42/44 expression by lapatinib . Consequently , we observed an increase in the Bax / Bcl 2 ratio and P38936 REA protein expression in cells exposed to the combination . Overall , our data showed that whatever the schedule and the cell line were , additive to synergistic interaction was achieved in our models . The optimal in vitro combination was finally tested in tumor-bearing mice . Our results fully confirmed that associating both drugs led to a 77 % reduction in tumor growth as compared with control animals in BT474 - xenografted models . Taken together , this non-clinical study shows that lapatinib and capecitabine modulate each other ' s molecular determinants of response and that concomitant dosing seems to be the optimal way to combine these drugs . Besides , modulation of TS expression by lapatinib makes its association with capecitabine a promising way to overcome breast cancers resistant in relation with TS overexpression .

Behavioral suppression induced by cannabinoids is due to activation of the arachidonic acid cascade in rats . DB00470 SUB ( THC ) is the principle psychoactive ingredient of marijuana and produces various psychoactive effects through the brain cannabinoid ( P21554 REA ) receptor . The P21554 REA receptor belongs to the seven-transmembrane domain family of G-protein-coupled receptors and is involved in the arachidonic acid cascade in the brain . Few reports have attempted to clarify the functional role of endogenous cannabinoid and the arachidonic acid cascade through the P21554 REA receptor using a behavioral paradigm . Therefore , in this study , we clarified the mechanism of cannabinoid-induced suppression of lever pressing in rats , focusing on the arachidonic acid cascade as a novel second messenger of P21554 REA receptor . Delta (8 ) - THC and the potent synthetic P21554 REA receptor agonist HU - 210 dose-dependently inhibited lever-pressing performance . The Delta (8 ) - THC-induced suppression was significantly antagonized by the cyclooxygenase ( P36551 REA ) inhibitors diclofenac ( 32 mg / kg , i . p . ) , aspirin ( 10 mg / kg , i . p . ) and indomethacin ( 10 mg / kg , i . p . ) . The suppressive effect of HU - 210 was also significantly antagonized by 32 mg / kg diclofenac . Prostaglandin E ( 2 ) ( 3.2 microg / rat , i . c . v . ) , the final product of the arachidonic acid cascade , significantly inhibited lever pressing similar to Delta (8 ) - THC and HU - 210 . In conclusion , we found that suppression of lever-pressing behavior induced by cannabinoids was mediated through activation of the arachidonic acid cascade via the P21554 REA receptor . Therefore , it is possible that the psychoactive effects of cannabinoid are due to an increase in the formation of PGE ( 2 ) in the brain .

Effects of delta 9 - THC on P01282 REA - induced prolactin secretion in anterior pituitary cultures : evidence for the presence of functional cannabinoid P21554 REA receptors in pituitary cells . Peripheral administration of cannabinoid P21554 REA receptor agonists to laboratory rats induce a brief rise in plasma prolactin ( PRL ) levels followed by a prolonged decrease in PRL secretion from the pituitary . While the inhibitory component of this biphasic response depends on the cannabinoid-induced activation of dopamine release from hypothalamic terminals located in the median eminence , the neurobiological mechanisms underlying the activation phase of PRL release remains to be explained . In the present study the possible direct effect of the cannabinoid receptor agonist DB00470 SUB ( THC ) on prolactin secretion and DB02527 accumulation was examined in anterior pituitary cultures . THC ( 0.1 and 1 microM ) increased DB02527 levels , and induced PRL release ( 1 and 10 mu ) . THC did not affect vasoactive intestinal peptide ( P01282 REA , 0.5 microM ) induced DB02527 accumulation in pituitary cultures , showing additive effects at THC 1 microM concentration . However , THC did prevent P01282 REA - dependent increases in prolactin secretion . These results indicate that THC , through a direct pituitary action , activates both the synthesis of DB02527 and PRL release and interferes with intracellular mechanisms involved in PRL secretion by P01282 REA . These actions could be mediated through cannabinoid P21554 REA receptors which were found to be present in anterior pituitary cells , including lactotrophs , as revealed by immunocytochemistry with a specific polyclonal antibody raised against the P21554 REA receptor protein .

Nicotinic alpha 7 receptors as a new target for treatment of cannabis abuse . Increasing use of cannabis makes the search for medications to reduce cannabis abuse extremely important . Here , we show that homomeric alpha 7 nicotinic receptors are novel molecular entities that could be targeted in the development of new drugs for the treatment of cannabis dependence . In rats , systemic administration of the selective alpha 7 nicotinic acetylcholine receptor antagonist methyllycaconitine ( MLA ) , but not the selective heteromeric non-alpha 7 nicotinic acetylcholine receptor antagonist dihydrobetaerythroidine , ( 1 ) antagonized the discriminative effects of DB00470 SUB ( THC ) , the main active ingredient in cannabis , ( 2 ) reduced intravenous self-administration of the synthetic cannabinoid P21554 REA receptor agonist WIN 55,212- 2 [ ( R ) - ( + ) - [ 2,3- dihydro - 5 - methyl - 3 [ ( 4 - morpholinyl ) methyl ] pyrrolo [ 1,2 , 3 - de ] -1,4- benzoxazinyl ] - ( 1 - naphthalenyl ) methanone , mesylate salt ] , and ( 3 ) decreased THC-induced dopamine elevations in the shell of the nucleus accumbens . Altogether , our results indicate that blockade of alpha 7 nicotinic receptors reverses abuse-related behavioral and neurochemical effects of cannabinoids . Importantly , MLA reversed the effects of cannabinoids at doses that did not produce depressant or toxic effects , further pointing to alpha 7 nicotinic antagonists as potentially useful agents in the treatment of cannabis abuse in humans .

DB06155 , a selective cannabinoid P21554 REA receptor antagonist , inhibits atherosclerosis in P01130 REA - deficient mice . OBJECTIVE : The objective of this study was to determine whether the potent selective cannabinoid receptor - 1 antagonist rimonabant has antiatherosclerotic properties . METHODS AND RESULTS : DB06155 ( 50 mg / kg / d in the diet ) significantly reduced food intake ( from 3.35+ / - . 04 to 2.80+ / -0.03 g / d ) , weight gain ( from 14.6+ / -0.7 g to -0.6+ / -0.3 g ) , serum total cholesterol ( from 8.39+ / -0.54 to 5.32+ / -0.18 g / L ) , and atherosclerotic lesion development in the aorta ( from 1.7+ / -0.22 to 0.21+ / -0.037 mm ( 2 ) ) and aortic sinus ( from 101,000+ / - 7800 to 27,000+ / - 2900 microm ( 2 ) ) of P01130 REA ( - / - ) mice fed a Western-type diet for 3 months . DB06155 also reduced plasma levels of the proinflammatory cytokines P13500 REA and IL12 by 85 % ( P < 0.05 ) and 76 % ( P < 0.05 ) , respectively . Pair-fed animals had reduced weight gain ( 6.2+ / -0.6 g gain ) , but developed atherosclerotic lesions which were as large as those of untreated animals , showing that the antiatherosclerotic effect of rimonabant is not related to reduced food intake . Interestingly , rimonabant at a lower dose ( 30 mg / kg / d in the diet ) reduced atherosclerosis development in the aortic sinus ( from 121,000+ / -20,000 to 62,000+ / -11,000 microm ( 2 ) , 49 % reduction , P < 0.05 ) , without affecting serum total cholesterol ( 7.8+ / -0.7 g / L versus 8.1+ / -1.3 g / L in the control group ) . DB06155 decreased lipopolysaccharide ( LPS ) - and IL1beta - induced proinflammatory gene expression in mouse peritoneal macrophages in vitro as well as thioglycollate-induced recruitment of macrophages in vivo ( 10 mg / kg , p . o . bolus ) . CONCLUSIONS : These results show that rimonabant has antiatherosclerotic effects in P01130 REA ( - / - ) mice . These effects are partly unrelated to serum cholesterol modulation and could be related to an antiinflammatory effect .

Elevated retinol binding protein 4 induces apolipoprotein B production and associates with hypertriglyceridemia . CONTEXT AND OBJECTIVE : A high level of retinol binding protein 4 ( P02753 REA ) is reported to be associated with insulin resistance in humans . However , evidence from large-scale populations about the relationship between serum P02753 REA and metabolic phenotypes is scarce . In the present study , we aimed to evaluate serum P02753 REA distribution and its association with metabolic phenotypes among middle-aged and elderly Chinese . DESIGN AND PARTICIPANTS : Serum concentrations of P02753 REA in a cross-sectional sample of 2780 Chinese population aged 50-70 years old in Guangzhou were measured by ELISA . RESULTS : The mean of serum P02753 REA concentration was 28.04 μg / mL for male and 37.76 μg / mL for female ( P < . 01 ) , respectively . Circulating P02753 REA was positively correlated with serum triglyceride and apolipoprotein B ( apoB ) concentrations . The odds ratio ( OR ) was substantially higher for hypertriglyceridemia ( OR , 3.26 ; 95 % confidence interval , 2.36- 4.51 ) in the highest P02753 REA quartile compared with those in the lowest quartile after multiple adjustment for confounders . Furthermore , serum P02753 REA was significantly associated with fasting glucose , insulin levels , and homeostasis model assessment index-insulin resistance ( HOMA-IR ) . Moreover , we showed that P02753 REA enhanced microsomal triglyceride transfer protein ( P55157 REA ) expression and activity via up-regulation of protein disulfide isomerase ( P07237 REA ) , suppressed low-density lipoprotein receptor ( P01130 REA ) expression , and impaired insulin-signaling pathway , leading to inductions in apoB secretion both in vitro and in vivo . CONCLUSIONS : Elevated circulating P02753 REA concentrations were associated with higher risk of hypertriglyceridemia by inducing the secretion of triglyceride-rich apoB-containing lipoproteins .

Microsomal transfer protein ( P55157 REA ) inhibition-a novel approach to the treatment of homozygous hypercholesterolemia . Homozygous familial hypercholesterolemia ( HoFH ) represents the most severe lipoprotein disorder , generally attributable to mutation ( s ) of the low-density lipoprotein receptor ( LDL-R ) , i . e . autosomal dominant hypercholesterolemia type 1 ( P07327 REA ) . Much lower percentages are due to alterations of apolipoprotein B ( P00325 REA ) , or gain-of-function mutations of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) ( P00326 REA ) . In certain geographical areas a significant number of patients may be affected by an autosomal recessive hypercholesterolemia ( Q5SW96 ) . Mutations may be also combined ( two mutations of the same gene , compound heterozygosity ) , or two in different genes ( double heterozygosity ) . Among the most innovative therapeutic approaches made available recently , inhibitors of the microsomal transfer protein ( P55157 REA ) system have shown a high clinical potential . P55157 REA plays a critical role in the assembly / secretion of very-low-density lipoproteins ( VLDL ) , and its absence leads to apo B deficiency . P55157 REA antagonists dramatically lower LDL-cholesterol ( LDL-C ) in animals , although a reported increase of liver fat delayed their clinical development . DB08827 MEN , the best-studied P55157 REA inhibitor , reduces LDL-C by 50 % or more in HoFH patients , with modest , reversible , liver steatosis . Recent US approval has confirmed an acceptable tolerability , provided patients adhere to a strictly low-fat regimen . There are no clinical data on atherosclerosis reduction / regression , but animal models provide encouraging results .

Effects of DB00470 SUB and ( R ) - methanandamide on open-field behavior in rats . This study compared the effects of ( R ) - methanandamide , an analog of the mammalian brain constituent anandamide , and DB00470 SUB on the open-field behavior of male Sprague-Dawley rats . Rats were individually housed with free access to food and water . Animals were treated with 0 , 1 , 3 , and 5.6 mg / kg DB00470 SUB given i . p . 30 min pre-session ; and 0 , 3 , 10 , and 18 mg / kg ( R ) - methanandamide , 15 min pre-session . The behavioral categories recorded were ambulation ( the number of squares crossed ) , rearing ( the number of times the rat stood erect on its hind-legs ) , latency ( the time in seconds to leave the starting area , the circle in the center of the field ) , circling ( the number of times the animal turned around its vertical axis , 0.5 point given for each 180 degrees turn ) , grooming ( the number of cleaning bouts ) , urination and defecation ( the number of urination spots and fecal boli deposited during the 5 min observation period ) . Delta - 9 - tetrahydrocannabinol was more potent than ( R ) - methanandamide , but otherwise the effects of DB00470 SUB and ( R ) - methanandamide were similar , with one exception ; whereas DB00470 SUB produced dose-related increases in circling , ( R ) - methanandamide did not increase circling over the doses examined . The DB00470 SUB - induced increase in circling was blocked by the central cannabinoid receptor P21554 REA antagonist SR 141716 . The differential effects with regard to circling may indicate that there are qualitative behavioral differences in the effects of DB00470 SUB and ( R ) - methanandamide .

The cannabinoid P21554 REA antagonists SR 141716A and AM 251 suppress food intake and food-reinforced behavior in a variety of tasks in rats . Cannabinoid P21554 REA receptor agonists , including DB00470 SUB ( Delta 9 - THC ) ( the main psychoactive ingredient in marijuana ) have been shown to increase feeding in rats and humans . Conversely , it has been reported that acute administration of the P21554 REA receptor antagonist SR 141716A reduces food intake in rats . Based upon this observation , it has been suggested that P21554 REA antagonists could be useful as appetite suppressant drugs . The present studies were designed to provide a detailed examination of the effects of P21554 REA antagonists on food intake across a range of paradigms . Two P21554 REA antagonists ( SR 141716A and AM 251 ) were administered to rats trained on fixed-ratio schedules with two different ratio requirements ( fixed-ratio 1 and fixed-ratio 5 ) . Both drugs produced a dose-dependent decrease in lever pressing , and had a relatively long duration of action ( T1 / 2 : SR 141716A , 15.1 h ; AM 251 , 22.0 h ) . Furthermore , intake of three diets with differing macronutrient composition ( lab chow , high fat , high carbohydrate ) was studied . Both drugs significantly suppressed intake of all three foods , and there were no significant interactions between drug dose and diet type . These findings support the hypothesis that P21554 REA receptor antagonists could be useful pharmacological tools for the suppression of appetite .

Tumor-derived P01730 REA ( + ) CD25 ( + ) regulatory T cell suppression of dendritic cell function involves TGF-beta and P22301 REA . P01730 REA ( + ) CD25 ( + ) regulatory T cells have been characterized as a critical population of immunosuppressive cells . They play a crucial role in cancer progression by inhibiting the effector function of P01730 REA ( + ) or CD8 ( + ) T lymphocytes . However , whether regulatory T lymphocytes that expand during tumor progression can modulate dendritic cell function is unclear . To address this issue , we have evaluated the inhibitory potential of P01730 REA ( + ) CD25 ( + ) regulatory T cells from mice bearing a P11274 REA - P00519 REA ( + ) leukemia on bone marrow-derived dendritic cells . We present data demonstrating that P01730 REA ( + ) CD25 ( + ) FoxP 3 ( + ) regulatory T cells from tumor-bearing animals impede dendritic cell function by down-regulating the activation of the transcription factor NF-kappaB . The expression of the co-stimulatory molecules P33681 REA , P42081 REA and P25942 REA , the production of P01375 REA , IL - 12 , and P13501 REA / RANTES by the suppressed DC is strongly down-regulated . The suppression mechanism requires TGF-beta and P22301 REA and is associated with induction of the Smad signaling pathway and activation of the P40763 REA transcription factor .

Differential effects of delta 9 - tetrahydrocannabinol and methanandamide in P21554 REA knockout and wild-type mice . Mice devoid of P21554 REA cannabinoid receptors ( P21554 REA - / - mice ) provide a unique opportunity to further investigate the role of P21554 REA receptors in exocannabinoid and endocannabinoid effects . P21554 REA - / - mice ( N = 18 ) and their wild-type littermates ( P21554 REA + / + mice ; N = 12 ) were placed in standard mouse operant chambers and trained to lever press under a fixed ratio 10 schedule of reinforcement . When stable lever press responding under the fixed ratio 10 schedule had been established , cannabinoids and noncannabinoids were administered to both groups . P21554 REA + / + mice acquired the lever press response more readily than P21554 REA - / - mice . Delta ( 9 ) - DB00470 SUB ( Delta ( 9 ) - THC ) decreased lever press responding in P21554 REA + / + mice only , whereas methanandamide , a metabolically stable endocannabinoid analog , produced similar response rate decreases in both genotypic groups . Similar to Delta ( 9 ) - THC , another endocannabinoid analog , ( R ) - ( 20 - cyano -16,16- dimethyl docosa-cis -5,8 , 11,14- tetraeno ) - 1 ' - hydroxy - 2 ' - propylamine ( O - 1812 ) , decreased responding in P21554 REA + / + mice , but not in P21554 REA - / - mice . The P21554 REA receptor antagonist N - ( piperidin - 1 - yl ) - 5 - ( 4 - chlorophenyl ) - 1 - ( 2,4- dichlorophenyl - 4 - methyl - 1H - pyrazole - 3 - carboxamide hydrochloride ( SR141716A ) blocked the effects of Delta ( 9 ) - THC , but not those of methanandamide . Because methanandamide binds poorly to CB2 receptors , these results suggest possible non - P21554 REA , non-CB 2 mechanisms of action for methanandamide-induced behavioral disruption of lever press responding . DB00898 and morphine elicited greater response decreases in P21554 REA - / - mice than in P21554 REA + / + mice , suggesting a possible role of P21554 REA receptors in the rate disruptive effects of these drugs . In contrast , diazepam did not produce between group differences , suggesting that P21554 REA receptors are not involved in diazepam-induced disruption of lever press responding .

Distribution of cannabinoid receptors in the central and peripheral nervous system . P21554 REA cannabinoid receptors appear to mediate most , if not all of the psychoactive effects of DB00470 SUB and related compounds . This G protein-coupled receptor has a characteristic distribution in the nervous system : It is particularly enriched in cortex , hippocampus , amygdala , basal ganglia outflow tracts , and cerebellum - - a distribution that corresponds to the most prominent behavioral effects of cannabis . In addition , this distribution helps to predict neurological and psychological maladies for which manipulation of the endocannabinoid system might be beneficial . P21554 REA receptors are primarily expressed on neurons , where most of the receptors are found on axons and synaptic terminals , emphasizing the important role of this receptor in modulating neurotransmission at specific synapses . While our knowledge of P21554 REA localization in the nervous system has advanced tremendously over the past 15 years , there is still more to learn . Particularly pressing is the need for ( 1 ) detailed anatomical studies of brain regions important in the therapeutic actions of drugs that modify the endocannabinoid system and ( 2 ) the determination of the localization of the enzymes that synthesize , degrade , and transport the endocannabinoids .

Delta ( 9 ) - DB00470 SUB enhances MCF - 7 cell proliferation via cannabinoid receptor-independent signaling . We recently reported that Delta ( 9 ) - tetrahydrocannabinol ( Delta ( 9 ) - THC ) has the ability to stimulate the proliferation of human breast carcinoma MCF - 7 cells . However , the mechanism of action remains to be clarified . The present study focused on the relationship between receptor expression and the effects of Delta ( 9 ) - THC on cell proliferation . RT-PCR analysis demonstrated that there was no detectable expression of CB receptors in MCF - 7 cells . In accordance with this , no effects of cannabinoid 1/2 ( P21554 REA / 2 ) receptor antagonists and pertussis toxin on cell proliferation were observed . Although MCF - 7 cell proliferation is suggested to be suppressed by Delta ( 9 ) - THC in the presence of CB receptors , it was revealed that Delta ( 9 ) - THC could exert upregulation of living cells in the absence of the receptors . Interestingly , Delta ( 9 ) - THC upregulated human epithelial growth factor receptor type 2 ( P04626 REA ) expression , which is known to be a predictive factor of human breast cancer and is able to stimulate cancer cells as well as MCF - 7 cells . DB00970 - treatment interfered with the upregulation of P04626 REA and cell proliferation by cannabinoid . Taken together , these studies suggest that , in the absence of CB receptors , Delta ( 9 ) - THC can stimulate the proliferation of MCF - 7 cells by modulating , at least in part , P04626 REA transcription .

[ Neuropsychopharmacology of DB00470 SUB ] . Today , the main route of introduction of tetrahydrocannabinol ( THC ) , the main active substance of cannabis , into the human body is via the lungs , from smokes produced by combustion of a haschich-tobacco mixture . The use of a water pipe ( nargileh-like ) intensifies its fast supply to the body . THC reaches the brain easily where it stimulates P21554 REA receptors ; their ubiquity underlies a wide variety of effects . THC disappears from extracellular spaces by dissolving in lipid rich membranes , and not by excretion from the body . This is followed by a slow release , leading to long lasting effects originating from brain areas containing a large proportion of spare receptors ( " reserve receptors " ) . Far from mimicking the effects of endocannabinoids , THC caricatures and disturbs them . It induces both psychical and physical dependencies , but the perception of withdrawal is weak on account of its very slow elimination . THC disturbs cognition . Acutely , it develops anxiolytic - and antidepressant-like effects , which causes a lot of users to abuse THC , thus leading to a tolerance ( desensitization of P21554 REA receptors ) making anxiety and depression to reappear more intensely than originally . THC has close relationships with schizophrenia . It incites to tobacco , alcohol and heroine abuses .

Construction of a steric map of the binding pocket for cannabinoids at the cannabinoid receptor . In order to gain information about the topology of the brain cannabinoid receptor ( P21554 REA ) , a Receptor Steric ( RS ) Map for cannabinoids at this receptor was calculated . The classical cannabinoids ( - ) - 11 - hydroxy - DB00470 SUB ( P04264 REA = 210 + / - 56 nM ) , ( - ) - 9 - nor - 9 - beta-hydroxy-hexahydrocannabinol ( P04264 REA = 124 + / - 17 nM ) , nabilone ( P04264 REA = 120 + / - 13 nM ) , and the non-classical cannabinoid , CP -55,244 ( P04264 REA = 1.4 + / - . 3 nM ) were used as template molecules . The RS map was obtained as the union of the van der Waals ' volumes of only those accessible conformers identified by P08253 REA calculations that were able to clear a region of steric interference at the P21554 REA receptor previously characterized by us [ Reggio , P . H . , Panu , A . M . and Miles , S . ( 1993 ) , J . Med . Chem . , 36 , 1761-1771 ] . The utility of the RS Map was explored by screening the accessible conformers of the classical cannabinoid , cannabinol ( CBN ) , ( P04264 REA = 3200 + / - 450 nM ) , for its ability to fit within the RS map . Only the global minimum energy conformer of CBN ( 53.2 % abundance at 298K ) was able to fit within the RS map . These results imply that one reason for the reduced affinity of CBN may be that only 53.2 % of CBN molecules are shaped properly to fit in the binding pocket for cannabinoids at the P21554 REA receptor .

Sex-specific alterations in hippocampal cannabinoid 1 receptor expression following adolescent DB00470 SUB treatment in the rat . Marijuana use by adolescents has been on the rise since the early 1990s . With recent legalization and decriminalization acts passed , cannabinoid exposure in adolescents will undoubtedly increase . Human studies are limited in their ability to examine underlying changes in brain biochemistry making rodent models valuable . Studies in adult and adolescent animals show region and sex specific downregulation of the cannabinoid 1 ( P21554 REA ) receptor following chronic cannabinoid treatment . However , although sex-dependent changes in behavior have been observed during the drug abstinence period following adolescent cannabinoid exposure , little is known about P21554 REA receptor expression during this critical time . In order to characterize P21554 REA receptor expression following chronic adolescent Δ - 9 - tetrahydrocannabinol ( THC ) exposure , we used [ ( 3 ) H ] CP55 , 940 binding to assess P21554 REA receptor expression in the dentate gyrus and areas P00915 REA , P00918 REA , and P07451 REA of the hippocampus in both male and female adolescent rats at both 24h and 2 weeks post chronic THC treatment . Consistent with other reported findings , we found downregulation of the P21554 REA receptor in the hippocampal formation at 24h post treatment . While this downregulation persisted in both sexes following two weeks of abstinence in the P00918 REA region , in females , this downregulation also persisted in areas P00915 REA and P07451 REA . Expression in the dentate gyrus returned to the normal range by two weeks . These data suggest that selective regions of the hippocampus show persistent reductions in P21554 REA receptor expression and that these reductions are more widespread in female compared to male adolescents .

Delta 9 - tetrahydrocannabinol is a full agonist at P21554 REA receptors on GABA neuron axon terminals in the hippocampus . Marijuana impairs learning and memory through actions of its psychoactive constituent , DB00470 SUB ( Delta ( 9 ) - THC ) , in the hippocampus , through activation of cannabinoid P21554 REA receptors ( CB1R ) . CB1Rs are found on glutamate and GABA neuron axon terminals in the hippocampus where they control neurotransmitter release . Previous studies suggest that Delta ( 9 ) - THC is a partial agonist of CB1Rs on glutamate axon terminals in the hippocampus , whereas its effects on GABA terminals have not been described . Using whole-cell electrophysiology in brain slices from C57BL6 / J mice , we examined Delta ( 9 ) - THC effects on synaptic GABA IPSCs and postsynaptic GABA currents elicited by laser-induced photo-uncaging ( photolysis ) of alpha-carboxy - 2 - nitrobenzyl ( P63098 REA ) caged GABA . Despite robust inhibition of synaptic IPSCs in wildtype mice by the full synthetic agonist WIN 55,212- 2 , using a Tween - 80 and DB01093 vehicle , Delta ( 9 ) - THC had no effects on IPSCs in this , or in a low concentration of another vehicle , randomly-methylated beta-cyclodextrin ( RAMEB , 0.023 % ) . However , IPSCs were inhibited by Delta ( 9 ) - THC in 0.1 % RAMEB , but not in neurons from CB1R knockout mice . Whereas Delta ( 9 ) - THC did not affect photolysis-evoked GABA currents , these responses were prolonged by a GABA uptake inhibitor . Concentration-response curves revealed that the maximal effects of Delta ( 9 ) - THC and WIN 55,212- 2 were similar , indicating that Delta ( 9 ) - THC is a full agonist at CB1Rs on GABA axon terminals . These results suggest that Delta ( 9 ) - THC inhibits GABA release , but does not directly alter GABA ( A ) receptors or GABA uptake in the hippocampus . Furthermore , full agonist effects of Delta ( 9 ) - THC on IPSCs likely result from a much higher expression of CB1Rs on GABA versus glutamate axon terminals in the hippocampus .

[ Cannabis use disorder and treatment of dependence ] . Cannabis , known as marijuana , has been used illicit drug by young people in the world . In our country , the number of user for cannabis is recently increased gradually . It has been suggested that regular use of cannabis might induce several adverse effects such as dependence syndrome , because DB00470 SUB ( THC ) , a primary psychoactive component of cannabis , stimulates brain-reward areas through the activation of cannabinoid ( P21554 REA ) receptor and induce drug-seeking behavior . Therefore , it is necessary to investigate and establish the medications for cannabis dependence . In fact , controlled laboratory studies and small open-label clinical studies have shown that several candidates of medications for cannabinoid dependence are identified . Further investigation in controlled clinical trials may produce the therapeutic benefit for treatment about cannabis-related problems .

P01308 REA - like growth factor - 1 receptor signaling increases the invasive potential of human epidermal growth factor receptor 2 - overexpressing breast cancer cells via Src-focal adhesion kinase and forkhead box protein M1 . Resistance to the human epidermal growth factor receptor ( P04626 REA ) - targeted antibody trastuzumab is a major clinical concern in the treatment of P04626 REA - positive metastatic breast cancer . Increased expression or signaling from the insulin-like growth factor - 1 receptor ( IGF - 1R ) has been reported to be associated with trastuzumab resistance . However , the specific molecular and biologic mechanisms through which IGF - 1R promotes resistance or disease progression remain poorly defined . In this study , we found that the major biologic effect promoted by IGF - 1R was invasion , which was mediated by both Src-focal adhesion kinase ( Q05397 REA ) signaling and Q08050 REA ( FoxM 1 ) . Cotargeting IGF - 1R and P04626 REA using either IGF - 1R antibodies or IGF - 1R short hairpin RNA in combination with trastuzumab resulted in significant but modest growth inhibition . Reduced invasion was the most significant biologic effect achieved by cotargeting IGF - 1R and P04626 REA in trastuzumab-resistant cells . Constitutively active Src blocked the anti-invasive effect of IGF - 1R / P04626 REA cotargeted therapy . Furthermore , knockdown of FoxM 1 blocked DB01277 - mediated invasion , and dual targeting of IGF - 1R and P04626 REA reduced expression of FoxM 1 . Re-expression of FoxM 1 restored the invasive potential of IGF - 1R knockdown cells treated with trastuzumab . Overall , our results strongly indicate that therapeutic combinations that cotarget IGF - 1R and P04626 REA may reduce the invasive potential of cancer cells that are resistant to trastuzumab through mechanisms that depend in part on Src and FoxM 1 .

Role of phospholipase D2 in the agonist-induced and constitutive endocytosis of G-protein coupled receptors . We have recently shown that the mu-opioid receptor [ P35372 REA , also termed mu-opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 REA ) , a phospholipid-specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 REA ) 293 cells co-expressing P35372 REA and O14939 REA , treatment with ( D-Ala 2 , Me Phe 4 , Glyol 5 ) enkephalin ( DAMGO ) led to an increase in O14939 REA activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 REA . In contrast , a C-terminal splice variant of the mu-opioid receptor ( MOR 1D , also termed MOP ( 1D ) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR 1D also mediates an agonist-independent ( constitutive ) O14939 REA - activation facilitating agonist-induced and constitutive receptor endocytosis . Inhibition of O14939 REA activity by over-expression of a dominant negative O14939 REA ( nPLD 2 ) blocked the constitutive O14939 REA activation and impaired the endocytosis of MOR 1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta-opioid receptor [ Q8IXH6 , also termed delta-opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 REA ) is also mediated by a O14939 REA - dependent pathway . These data indicate the generally important role for O14939 REA in the regulation of agonist-dependent and agonist-independent G protein-coupled receptor ( GPCR ) endocytosis .

( + ) - DB09061 analogues which bind cannabinoid receptors but exert peripheral activity only . Delta 9 - DB00470 SUB ( Delta 9 - THC ) and ( - ) - cannabidiol are major constituents of the Cannabis sativa plant with different pharmacological profiles : ( - ) - Delta 9 - tetrahydrocannabinol , but not ( - ) - cannabidiol , activates cannabinoid P21554 REA and CB2 receptors and induces psychoactive and peripheral effects . We have tested a series of ( + ) - cannabidiol derivatives , namely , ( + ) - cannabidiol - Q03001 REA ( Q03001 REA -1,1- dimethylheptyl - ) , ( + ) - 7 - OH-cannabidiol - Q03001 REA , ( + ) - 7 - OH - cannabidiol , ( + ) - 7 - COOH - cannabidiol and ( + ) - 7 - COOH-cannabidiol - Q03001 REA , for central and peripheral ( intestinal , antiinflammatory and peripheral pain ) effects in mice . Although all ( + ) - cannabidiols bind to cannabinoid P21554 REA and CB2 receptors , only ( + ) - 7 - OH-cannabidiol - Q03001 REA was centrally active , while all ( + ) - cannabidiol analogues completely arrested defecation . The effects of ( + ) - cannabidiol - Q03001 REA and ( + ) - 7 - OH-cannabidiol - Q03001 REA were partially antagonized by the cannabinoid P21554 REA receptor antagonist N - ( piperidiny - 1 - yl ) - 5 - ( 4 - chlorophenyl ) - 1 - ( 2,4- dichlorophenyl ) - 4 - methyl - 1H - pyrazole - 3 - carboxamide ( SR141716 ) , but not by the cannabinoid CB2 receptor antagonist N - [ - ( 1S ) - endo -1,3 , 3 - trimethil bicyclo [ 2.2 . 1 ] heptan - 2 - yl - 5 - ( 4 - chloro - 3 - methylphenyl ) - 1 - ( 4 - methylbenzyl ) - pyrazole - 3 - carboxamide ( SR144528 ) , and had no effect on P21554 REA ( - / - ) receptor knockout mice . ( + ) - DB09061 - Q03001 REA inhibited the peripheral pain response and arachidonic-acid-induced inflammation of the ear . We conclude that centrally inactive ( + ) - cannabidiol analogues should be further developed as antidiarrheal , antiinflammatory and analgesic drugs for gastrointestinal and other peripheral conditions .

Effect of Nelumbo nucifera Petal Extracts on Lipase , Adipogenesis , Adipolysis , and Central Receptors of Obesity . N . nucifera is one among the important medicinal plants assessed for its antiobesity action in various preclinical models . The present study was aimed at investigating the antiobesity effect of methanol and successive water extracts of petals of N . nucifera by studying its effect on adipogenesis , adipolysis , lipase , serotonin ( P28335 REA ) , cannabinoid ( P34972 REA ) , melanocyte concentrating hormone ( Q99705 REA ) , and melanocortin ( P32245 REA ) receptors . Both methanol and successive water extracts of N . nucifera petals had an effect on inhibition of lipid storage in adipocytes and on increasing lipolysis . N . nucifera petal methanol extract exhibited the concentration-dependent inhibitory effect on lipase activity with an IC50 value of 47 µg / mL . N . nucifera petal extracts showed evident agonist and antagonist activity towards P28335 REA and P34972 REA receptors , respectively , while it showed no effect towards Q99705 REA and P32245 REA receptors . Overall , methanol extract of N . nucifera petals showed better activity than successive water extract .

Nearly Complete Response of Brain Metastases from P04626 REA Overexpressing Breast Cancer with DB01259 MEN and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 REA overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 REA - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .

Oleocanthal inhibits proliferation and MIP - 1α expression in human multiple myeloma cells . Multiple myeloma ( MM ) is a plasma cell malignancy that causes devastating bone destruction by activating osteoclasts in the bone marrow milieu . MM is the second of all hematological malignancies . Thus , the search for new pharmacological weapons is under intensive investigation being MM a critically important public health goal . Recently , it has been demonstrated that macrophage inflammatory protein 1 - alpha ( MIP - 1 α ) is crucially involved in the development of osteolytic bone lesions in MM . Phenolic components of extra virgin olive oil are reported to have anti tumor activity . However , the underlying mechanisms and specific targets of extra virgin olive oil remain to be elucidated . In the present study , we investigated the effects of a recently isolated novel extra virgin olive oil polyphenol , oleocanthal , on the human multiple myeloma cell line Q5SW96 - 77 . Here we report that this natural compound has a remarkable in vitro activity by inhibiting MIP - 1 α expression and secretion in MM cells . In addition , we also demonstrated that oleocanthal inhibits MM cells proliferation by inducing the activation of apoptosis mechanisms and by down-regulating P27361 REA / 2 and AKT signal transduction pathways . This in vitro study suggests a therapeutic potential of oleocanthal in treating multiple myeloma .

Inhibition of THC-induced effects on the central nervous system and heart rate by a novel P21554 REA receptor antagonist AVE 1625 . P21554 REA antagonists such as AVE 1625 are potentially useful in the treatment of obesity , smoking cessation and cognitive impairment . Proof of pharmacological action of AVE 1625 in the brain can be given by antagonising the effects of DB00470 SUB ( THC ) , a P21554 REA / CB2 agonist . Inhibition of THC-induced effects by AVE 1625 was observed on Visual Analogue Scales ' alertness ' , ' feeling high ' , ' external perception ' , ' body sway ' and ' heart rate ' . Even the lowest dose of AVE 1625 20 mg inhibited most of THC-induced effects . AVE 1625 did not have any effect on psychological and behavioural parameters or heart rate by itself . After THC and AVE 1625 administration , changes on electroencephalography were observed . This study shows a useful method for studying the effects of P21554 REA antagonists . AVE 1625 penetrates the brain and antagonises THC-induced effects with doses at or above 20 mg .

Interactions between A - 9THC and capsaicin on isolated lamb bladder detrusor . A number of studies have demonstrated that capsaicin , a capsicum alkaloid , can affect isolated bladder tissue with either a relaxation or a contraction , depending on the species , by acting on Q8NER1 receptors . In a previous work on isolated lamb detrusor , we demonstrated that capsaicin generally produces a relaxation of the tissue ; this relaxation seems to be mediated by P8 0511 . Endogenous cannabinoids , such as anandamide , produce some of their actions by stimulating Q8NER1 receptors and this seems to cause the release of peptides , e . g . P8 0511 . The aim of this work was to ascertain whether a cannabinoid , DB00470 SUB ( delta - 9THC ) , was able to interfere with the response of the isolated lamb detrusor to capsaicin . A - 9THC , at concentrations between 1.6 x 10 ( - 7 ) and 1.3 x 10 ( - 6 ) M , displayed no activity on tissues . Instead , following delta - 9THC , most of the tissues responded to capsaicin with a contraction that was abolished by atropine ( 9.0 x 10 ( - 7 ) M ) . It has been reported that cannabinoids can inhibit the release of P8 0511 by stimulation of P21554 REA and CB2 cannabinoid receptors . Delta - 9THC could act stimulating these receptors and thus inhibiting P8 0511 release and vesical relaxation . The muscle relaxing component removal could favour the contracting component , usually not active .

Tolerance to chronic DB00470 SUB ( Δ⁹-THC ) in rhesus macaques infected with simian immunodeficiency virus . Although Δ⁹-THC has been approved to treat anorexia and weight loss associated with AIDS , it may also reduce well-being by disrupting complex behavioral processes or enhancing HIV replication . To investigate these possibilities , four groups of male rhesus macaques were trained to respond under an operant acquisition and performance procedure , and administered vehicle or Δ⁹-THC before and after inoculation with simian immunodeficiency virus ( SIV ( mac 251 ) , 100 TCID₅₀ / ml , i . v . ) . Prior to chronic Δ⁹-THC and SIV inoculation , 0.032- 0.32 mg / kg of Δ⁹-THC produced dose-dependent rate-decreasing effects and small , sporadic error-increasing effects in the acquisition and performance components in each subject . Following 28 days of chronic Δ⁹-THC ( 0.32 mg / kg , i . m . ) or vehicle twice daily , DB00470 SUB - treated subjects developed tolerance to the rate-decreasing effects , and this tolerance was maintained during the initial 7-12 months irrespective of SIV infection ( i . e . , + THC / - SIV , + THC / + SIV ) . Q8N1N2 necropsy was performed on all SIV subjects an average of 329 days post-SIV inoculation , with postmortem histopathology suggestive of a reduced frequency of CNS pathology as well as opportunistic infections in DB00470 SUB - treated subjects . Chronic Δ⁹-THC also significantly reduced CB - 1 and P34972 REA receptor levels in the hippocampus , attenuated the expression of a proinflammatory cytokine ( P13500 REA ) , and did not increase viral load in plasma , cerebrospinal fluid , or brain tissue compared to vehicle-treated subjects with SIV . Together , these data indicate that chronic Δ⁹-THC produces tolerance to its behaviorally disruptive effects on complex tasks while not adversely affecting viral load or other markers of disease progression during the early stages of infection .

Actions of DB00470 SUB in cannabis : relation to use , abuse , dependence . Cannabis use disorders have been recently identified as a relevant clinical issue : a subset of cannabis smokers seeks treatment for their cannabis use , yet few succeed in maintaining long-term abstinence . The rewarding and positive reinforcing effects of the primary psychoactive component of smoked cannabis , DB00470 SUB ( THC ) are mediated by the cannabinoid P21554 REA receptor . The P21554 REA receptor has also been shown to mediate cannabinoid dependence and expression of withdrawal upon cessation of drug administration , a phenomenon verified across species . This paper will review findings implicating the P21554 REA receptor in the behavioural effects of exogenous cannabinoids with a focus on cannabinoid dependence and reinforcement , factors that contribute to the maintenance of chronic cannabis smoking despite negative consequences . Opioidergic modulation of these effects is also discussed .

Effect of ( - ) - Delta ( 9 ) - tetrahydrocannabinoid on the hepatic redox state of mice . ( - ) - Delta ( 9 ) - DB00470 SUB ( Delta ( 9 ) - THC ) , a psychoactive component of marijuana , has been reported to induce oxidative damage in vivo and in vitro . In this study , we administered Delta ( 9 ) - THC to healthy C57BL / 6J mice aged 15 weeks in order to determine its effect on hepatic redox state . Mice were divided into 3 groups : Delta ( 9 ) - THC ( N = 10 ) , treated with 10 mg / kg body weight Delta ( 9 ) - THC daily ; VCtrl ( N = 10 ) , treated with vehicle [ 1:1 : 18 , cremophor EL ( polyoxyl 35 castor oil ) / ethanol / saline ] ; Ctrl ( N = 10 ) , treated with saline . Animals were injected ip twice a day with 5 mg / kg body weight for 10 days . Lipid peroxidation , protein carbonylation and DNA oxidation were used as biomarkers of oxidative stress . The endogenous antioxidant defenses analyzed were glutathione ( DB00143 ) levels as well as enzyme activities of superoxide dismutase , catalase , glutathione S-transferase , glutathione reductase , and glutathione peroxidase ( GPx ) in liver homogenates . The levels of mRNA of the cannabinoid receptors P21554 REA and CB2 were also monitored . Treatment with Delta ( 9 ) - THC did not produce significant changes in oxidative stress markers or in mRNA levels of P21554 REA and CB2 receptors in the liver of mice , but attenuated the increase in the selenium-dependent GPx activity ( Delta ( 9 ) - THC : 8 % ; VCtrl : 23 % increase ) and the DB00143 / oxidized DB00143 ratio ( Delta ( 9 ) - THC : 61 % ; VCtrl : 96 % increase ) , caused by treatment with the vehicle . Delta ( 9 ) - THC administration did not show any harmful effects on lipid peroxidation , protein carboxylation or DNA oxidation in the healthy liver of mice but attenuated unexpected effects produced by the vehicle containing ethanol / cremophor EL .

Involvement of sphingomyelin hydrolysis and the mitogen-activated protein kinase cascade in the Delta 9 - tetrahydrocannabinol-induced stimulation of glucose metabolism in primary astrocytes . The effects of cannabinoids on metabolic pathways and signal transduction systems were studied in primary cultures of rat astrocytes . Delta 9 - DB00470 SUB ( THC ) , the major active component of marijuana , increased the rate of glucose oxidation to CO2 as well as the rate of glucose incorporation into phospholipids and glycogen . These effects of THC were mimicked by the synthetic cannabinoid HU - 210 , and prevented by forskolin , pertussis toxin , and the P21554 REA receptor antagonist SR 141716 . THC did not affect basal DB02527 levels but partially antagonized the forskolin-induced elevation of intracellular DB02527 concentration . THC stimulated Q8NFH3 / Q8TCB0 mitogen-activated protein kinase ( MAPK ) activity , P04049 REA phosphorylation , and P04049 REA translocation to the particulate cell fraction . In addition , the MAPK inhibitor PD 098095 and the phosphoinositide 3 - kinase inhibitors wortmannin and LY 294002 were able to antagonize the THC-induced stimulation of glucose oxidation to CO2 , phospholipid synthesis and glycogen synthesis . The possible involvement of sphingomyelin breakdown in the metabolic effects of THC was studied subsequently . THC produced a rapid stimulation of sphingomyelin hydrolysis that was concomitant to an elevation of intracellular ceramide levels . This effect was prevented by SR 141716 . Moreover , the cell-permeable ceramide analog D-erythro-N-octanoylsphingosine , as well as exogenous sphingomyelinase , were able in turn to stimulate MAPK activity , to increase the amount of P04049 REA bound to the particulate cell fraction , and to stimulate glucose metabolism . The latter effect was prevented by PD 098059 and was not additive to that exerted by THC . Results thus indicate that THC produces a cannabinoid receptor-mediated stimulation of astrocyte metabolism that seems to rely on sphingomyelin hydrolysis and MAPK stimulation .

Opposite function of dopamine D1 and N-methyl-D-aspartate receptors in striatal cannabinoid-mediated signaling . It is well established that the cannabinoid and dopamine systems interact at various levels to regulate basal ganglia function . Although it is well known that acute administration of cannabinoids to mice can modify dopamine-dependent behaviors , the intraneuronal signaling pathways employed by these agents in the striatum are not well understood . Here we used knockout mouse models to examine the regulation of striatal extracellular-signal-regulated kinases 1 and 2 ( P27361 REA / 2 ) signaling by behaviorally relevant doses of cannabinoids . This cellular pathway has been implicated as a central mediator of drug reward and synaptic plasticity . In C57BL / 6J mice , acute administration of the cannabinoid agonists , ( - ) - 11 - hydroxydimethylheptyl-Δ 8 - tetrahydrocannabinol ( HU - 210 ) and DB00470 SUB ( Δ ( 9 ) - THC ) , promoted a dose - and time-dependent decrease in the phosphorylation of P27361 REA / 2 in dorsal striatum . Co-administration of the P21554 REA cannabinoid receptor antagonist N - ( Piperidin - 1 - yl ) - 5 - ( 4 - iodophenyl ) - 1 - ( 2,4- dichlorophenyl ) - 4 - methyl - 1H - pyrazole - 3 - carboxamide ( AM251 ) with HU - 210 prevented P27361 REA / 2 inactivation , indicating a requirement for activation of this receptor . In dopamine D1 receptor knockout animals treated with HU - 210 , the magnitude of the HU - 210 - dependent decrease in striatal P27361 REA / 2 signaling was greater than in wild-type controls . In contrast , HU - 210 administration to N-methyl-D-aspartate receptor knockdown mice was ineffective at promoting striatal P27361 REA / 2 inactivation . Genetic deletion of other potential P27361 REA / 2 mediators , the dopamine D2 receptors or β-arrestin - 1 or - 2 , did not affect the HU - 210 - induced modulation of P27361 REA / 2 signaling in the striatum . These results support the hypothesis that dopamine D1 receptors and N-methyl-D-aspartate receptors act in an opposite manner to regulate striatal P21554 REA cannabinoid receptor signal transduction .

Inhibition of recombinant human T-type calcium channels by Delta 9 - tetrahydrocannabinol and cannabidiol . Delta ( 9 ) - DB00470 SUB ( THC ) and cannabidiol ( DB09061 ) are the most prevalent biologically active constituents of Cannabis sativa . THC is the prototypic cannabinoid P21554 REA receptor agonist and is psychoactive and analgesic . DB09061 is also analgesic , but it is not a P21554 REA receptor agonist . Low voltage-activated T-type calcium channels , encoded by the Ca ( V ) 3 gene family , regulate the excitability of many cells , including neurons involved in nociceptive processing . We examined the effects of THC and DB09061 on human Ca ( V ) 3 channels stably expressed in human embryonic kidney 293 cells and T-type channels in mouse sensory neurons using whole-cell , patch clamp recordings . At moderately hyperpolarized potentials , THC and DB09061 inhibited peak Ca ( V ) 3.1 and Ca ( V ) 3.2 currents with IC ( 50 ) values of approximately 1 mum but were less potent on Ca ( V ) 3.3 channels . THC and DB09061 inhibited sensory neuron T-type channels by about 45 % at 1 mum . However , in recordings made from a holding potential of - 70 mV , 100 nm THC or DB09061 inhibited more than 50 % of the peak Ca ( V ) 3.1 current . THC and DB09061 produced a significant hyperpolarizing shift in the steady state inactivation potentials for each of the Ca ( V ) 3 channels , which accounts for inhibition of channel currents . Additionally , THC caused a modest hyperpolarizing shift in the activation of Ca ( V ) 3.1 and Ca ( V ) 3.2 . THC but not DB09061 slowed Ca ( V ) 3.1 and Ca ( V ) 3.2 deactivation and inactivation kinetics . Thus , THC and DB09061 inhibit Ca ( V ) 3 channels at pharmacologically relevant concentrations . However , THC , but not DB09061 , may also increase the amount of calcium entry following T-type channel activation by stabilizing open states of the channel .

Antiemetic and motor-depressive actions of CP55 , 940 : cannabinoid P21554 REA receptor characterization , distribution , and G-protein activation . Dibenzopyran ( Delta ( 9 ) - tetrahydrocannabinol ) and aminoalkylindole [ R ( + ) - [ 2,3- dihydro - 5 - methyl - 3 - [ ( morpholinyl ) methyl ] pyrolol [ 1,2 , 3 - de ] -1,4- benzoxazin-yl ] - ( 1 - naphthalenyl ) methanone mesylate ; ( WIN 55,212- 2 ) ] cannabinoids suppress vomiting produced by cisplatin via cannabinoid CB ( 1 ) receptors . This study investigates the antiemetic potential of the " nonclassical " cannabinoid CP55 , 940 [ 1alpha , 2beta - ( R ) - 5alpha ] - ( - ) - 5 - ( 1,1- dimethyl ) - 2 - [ 5 - hydroxy - 2 - ( 3 - hydroxypropyl ) cyclohexyl-phenol ] against cisplatin-induced vomiting and assesses the presence and functionality of cannabinoid CB ( 1 ) receptors in the least shrew ( Cryptotis parva ) brain . CP55 , 940 ( 0.025- 0.3 mg / kg ) reduced both the frequency of cisplatin-induced emesis ( ID ( 50 )= 0.025 mg / kg ) and the percentage of shrews vomiting ( ID ( 50 )= 0.09 mg / kg ) . CP55 , 940 also suppressed shrew motor behaviors ( ID ( 50 )= 0.06- 0.21 mg / kg ) at such doses . The antiemetic and motor-suppressant actions of CP55 , 940 were countered by SR141716A [ N-piperidino - 5 - ( 4 - chlorophenyl ) - 1 - ( 2,4- dichlorophenyl ) - DB01213 - 3 - carboxamide ] , indicating both effects are cannabinoid CB ( 1 ) receptor-mediated . Autoradiographic studies with [ 3H ] - SR141716A and [ 35S ] - GTPgammaS binding revealed that the distribution of the cannabinoid CB ( 1 ) receptor and its activation pattern are similar to rodent brain and significant levels are present in brain loci ( e . g . , nucleus tractus solitarius ( P30990 REA ) ) that control emesis . The affinity rank order of structurally diverse cannabinoid ligands for cannabinoid CB ( 1 ) receptor in shrew brain is similar to rodent brain : HU - 210 = CP55 , 940 = SR141716A > /= WIN 55,212- 2 > /= DB00470 SUB > methanandamide = HU - 211 = cannabidiol = 2 - arachidonoylglycerol . This affinity order is also similar and is highly correlated to the cannabinoid EC ( 50 ) potency rank order for GTPgammaS stimulation except WIN 55,212- 2 and DB00470 SUB potency order were reversed . The affinity and the potency rank order of tested cannabinoids were significantly correlated with their antiemetic ID ( 50 ) potency order against cisplatin-induced vomiting ( CP55 , 940 > WIN 55,212- 2 = DB00470 SUB ) as well as emesis produced by 2 - arachidonoylglycerol or SR141716A ( CP55 , 940 > WIN 55,212- 2 > DB00470 SUB ) .

The cannabinoid DB00470 SUB mediates inhibition of macrophage chemotaxis to RANTES / P13501 REA : linkage to the CB2 receptor . The chemotactic response of murine peritoneal macrophages to RANTES / P13501 REA was inhibited significantly following pretreatment with DB00470 SUB ( THC ) , the major psychoactive component in marijuana . Significant inhibition of this chemokine directed migratory response was obtained also when the full cannabinoid agonist CP55940 was used . The CB2 receptor-selective ligand O - 2137 exerted a robust inhibition of chemotaxis while the P21554 REA receptor-selective ligand ACEA had a minimal effect . The THC-mediated inhibition was reversed by the CB2 receptor-specific antagonist SR144528 but not by the P21554 REA receptor-specific antagonist SR141716A . In addition , THC treatment had a minimal effect on the chemotactic response of peritoneal macrophages from CB2 knockout mice . Collectively , these results suggest that cannabinoids act through the CB2 receptor to transdeactivate migratory responsiveness to RANTES / P13501 REA . Furthermore , the results suggest that the CB2 receptor may be a constituent element of a network of G protein-coupled receptor signal transductional systems , inclusive of chemokine receptors , that act coordinately to modulate macrophage migration .

Chronic DB00470 SUB treatment increases DB02527 levels and DB02527 - dependent protein kinase activity in some rat brain regions . When Delta ( 9 ) - tetrahydrocannabinol ( Delta ( 9 ) - THC , 15 mg / kg ) was injected intraperitoneally twice a day for 6 days , tolerance to its analgesic effect appeared to be complete . Chronic exposure to Delta ( 9 ) - THC caused a significant reduction in P21554 REA receptor binding in all brain areas that contain this receptor . Cannabinoid receptor density was markedly reduced in the cerebellum ( 52 % ) , hippocampus ( 40 % ) and globus pallidum ( 47 % ) compared to 30 % in the cortex and striatum . Chronic exposure enhanced the DB02527 pathway , as shown by the significant increase of DB02527 levels and PKA activity in the areas with receptor down-regulation ( cerebellum , striatum and cortex ) . We propose that the increase in DB02527 cascade is part of the biochemical basis of cannabinoid tolerance .

Cannabinoid agonists but not inhibitors of endogenous cannabinoid transport or metabolism enhance the reinforcing efficacy of heroin in rats . Accumulating evidence suggests that the endogenous cannabinoid system is involved in the reinforcing effects of heroin . In rats intravenously self-administering heroin , we investigated effects of cannabinoid P21554 REA receptor agonists and compounds that block transport or metabolism of the endogenous cannabinoid anandamide . The natural cannnabinoid P21554 REA receptor agonist DB00470 SUB ( THC , 0.3- 3 mg / kg i . p . ) did not alter self-administration of heroin under a fixed-ratio one ( FR1 ) schedule , except at a high 3 mg / kg dose which decreased heroin self-administration . Under a progressive-ratio schedule , however , THC dose-dependently increased the number of 50 mug / kg heroin injections self-administered per session and the maximal ratio completed ( break-point ) , with peak increases at 1 mg / kg THC . In addition , 1 mg / kg THC increased break-points and injections self-administered over a wide range of heroin injection doses ( 25-100 microg / kg ) , indicating an increase in heroin ' s reinforcing efficacy and not its potency . The synthetic cannabinoid P21554 REA receptor agonist WIN 55,212- 2 ( 0.3- 3 mg / kg i . p . ) had effects similar to THC under the progressive-ratio schedule . In contrast , AM - 404 ( 1-10 mg / kg i . p . ) , an inhibitor of transport of anandamide , and Q76M96 - 597 ( 0.01- 0.3 mg / kg i . p . ) , an inhibitor of the enzyme fatty acid amide hydrolase ( FAAH ) that degrades anandamide , or their combination , did not increase reinforcing efficacy of heroin at any dose tested . Thus , activation of cannabinoid P21554 REA receptors facilitates the reinforcing efficacy of heroin and this appears to be mediated by interactions between cannabinoid P21554 REA receptors and mu-opioid receptors and their signaling pathways , rather than by an opioid-induced release of endogenous cannabinoids .

DB01259 MEN - mediated cyclooxygenase - 2 expression via epidermal growth factor receptor / Q15717 interaction enhances the aggressiveness of triple-negative breast cancer cells . DB01259 MEN , a dual epidermal growth factor receptor ( P00533 REA ) / human epidermal growth factor receptor 2 ( P04626 REA ) kinase inhibitor , showed clinical benefits in advanced P04626 REA - positive breast cancer patients . Because some triple-negative breast cancers ( TNBCs ) frequently overexpress P00533 REA , the antitumor activity of lapatinib in such diseases was also tested . However , the results showed a worse event-free survival rate . It remains unknown whether and how lapatinib elicits the aggressiveness of such cancer cells . In this study , our results demonstrated that lapatinib facilitated axillary and lung metastases of triple-negative MDA-MB - 231 breast cancer cells without affecting their viability , leading to worse survival in orthotopic xenograft mice . The lapatinib-increased motility was attributed by the elevation of P00533 REA through the downregulation of microRNA - 7 and by the subsequent overexpression of cyclooxygenase - 2 ( P35354 REA ) . Strikingly , independent of its kinase activity , the elevated P00533 REA at least partly stabilized P35354 REA expression by enhancing the binding of Q15717 to P35354 REA mRNA . Our results suggest that lapatinib may increase the migration and invasion of MDA-MB - 231 cells by upregulating P00533 REA and P35354 REA through the downregulation of microRNA - 7 , providing a potential explanation for the worse clinical outcome of TNBC patients who receive lapatinib-based treatment . These findings also shed new light on the molecular mechanism of P35354 REA mRNA stabilization by P00533 REA in a kinase-independent manner .

Identification of an amino acid residue important for binding of methiothepin and sumatriptan to the human 5 - HT ( 1B ) receptor . Site-directed mutagenesis of the human P28222 REA receptor was performed to investigate the role of the amino acid residues cysteine 326 and tryptophan 327 in transmembrane region VI and aspartic acid 352 in transmembrane region VII in ligand binding . Binding studies were performed with the antagonist radioligand [ 3H ] GR125743 on mutant and wild-type receptors stably expressed in Chinese hamster ovary cells ( CHO ) - P04264 REA cells . Substitution of tryptophan 327 by alanine resulted in decreased affinities of all ligands tested . The most prominent changes in affinity were observed for the antagonist methiothepin and the antimigraine drug sumatriptan , which were reduced approximately 300 - and 60 - fold , respectively . Nevertheless , the affinity of 5 - HT remained the same . Replacement of the aspartic acid 352 by alanine reduced high-affinity binding of 5 - HT . Substitution of cysteine 326 by alanine had minor effects on ligand binding . Some of these results agree with the results from mutagenesis studies of the corresponding amino acids in other receptors . However , some notable differences also emerge showing that functional roles of individual amino acid residues must be tested experimentally in each receptor subtype .

CB2 receptors in the brain : role in central immune function . Recently , it has been recognized that the cannabinoid receptor CB2 may play a functionally relevant role in the central nervous system ( CNS ) . This role is mediated primarily through microglia , a resident population of cells in the CNS that is morphologically , phenotypically , and functionally related to macrophages . These cells also express the cannabinoid receptor P21554 REA . The P21554 REA receptor ( CB1R ) is constitutively expressed at low levels while the CB2 receptor ( CB2R ) is expressed at higher levels and is modulated in relation to cell activation state . The relatively high levels of the CB2R correspond with microglia being in ' responsive ' and ' primed ' states , suggesting the existence of a ' window ' of functional relevance during which activation of the CB2R modulates microglial activities . Signature activities of ' responsive ' and ' primed ' microglia are chemotaxis and antigen processing , respectively . The endocannabinoid 2 - arachidonylglycerol has been reported to stimulate a chemotactic response from these cells through the CB2R . In contrast , we have shown in vivo and in vitro that the exogenous cannabinoids DB00470 SUB and CP55940 inhibit the chemotactic response of microglia to Acanthamoeba culbertsoni , an opportunistic pathogen that is the causative agent of Granulomatous Amoebic Encephalitis , through activation of the CB2R . It is postulated that these exogenous cannabinoids superimpose an inhibitory effect on pro-chemotactic endocannabinoids that are elicited in response to Acanthamoeba . Furthermore , the collective results suggest that the CB2R plays a critical immune functional role in the CNS .

DB08827 MEN : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : DB08827 MEN ( Juxtapid , Aegerion Pharmaceuticals ) is an oral microsomal triglyceride transfer protein ( P55157 REA ) inhibitor indicated for the treatment of patients with HoFH , a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease . In clinical trials , the use of lomitapide alone or in combination with other lipid-lowering modalities reduced plasma concentrations of low-density lipoprotein cholesterol ( LDL-C ) by a mean of more than 50 % . DB08827 MEN is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels . DB08827 MEN undergoes hepatic metabolism via cytochrome P - 450 ( CYP ) isoenzyme 3A4 and interacts with P08684 REA substrates including atorvastatin and simvastatin ; dose adjustment is recommended when lomitapide is used concurrently with these agents . In patients receiving concomitant warfarin , the International Normalized Ratio ( INR ) should be closely monitored , as lomitapide use may increase INR values . The recommended initial dosage of lomitapide is 5 mg once daily , with subsequent upward dose adjustment at specified intervals according to tolerability . DB08827 MEN is contraindicated in patients with moderate-to-severe liver disease , patients with sustained abnormal liver function tests , patients taking strong or moderate P08684 REA inhibitors , and pregnant patients . CONCLUSION : DB08827 MEN is an oral P55157 REA inhibitor approved for the treatment of HoFH . This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL-C goal or can not tolerate statin therapy .

Cannabinoid receptors and their endogenous ligands . Delta 9 - DB00470 SUB , a major psychoactive component of marijuana , has been shown to interact with specific cannabinoid receptors , thereby eliciting a variety of pharmacological responses in experimental animals and human . In 1990 , the gene encoding a cannabinoid receptor ( P21554 REA ) was cloned . This prompted the search for endogenous ligands . In 1992 , N-arachidonoylethanolamine ( anandamide ) was isolated from pig brain as an endogenous ligand , and in 1995 , 2 - arachidonoylglycerol was isolated from rat brain and canine gut as another endogenous ligand . Both anandamide and 2 - arachidonoylglycerol exhibit various cannabimimetic activities . The results of structure-activity relationship experiments , however , revealed that 2 - arachidonoylglycerol , but not anandamide , is the intrinsic natural ligand for the cannabinoid receptor . 2 - Arachidonoylglycerol is a degradation product of inositol phospholipids that links the function of cannabinoid receptors with the enhanced inositol phospholipid turnover in stimulated tissues and cells . The possible physiological roles of cannabinoid receptors and 2 - arachidonoylglycerol in various mammalian tissues such as those of the nervous system are discussed .

Association study of a cannabinoid receptor gene ( P21554 REA ) polymorphism and schizophrenia . Cannabis can induce schizophrenic-like symptoms in healthy individuals . A principal active ingredient of cannabis , DB00470 SUB , acts in the brain on a specific receptor , termed the cannabinoid receptor 1 ( P21554 REA ) . The human gene for P21554 REA is mapped to chromosome 6q14 - 15 , and linkage studies have produced evidence for a schizophrenia-susceptibility locus in this region . To explore a possible role for P21554 REA in the pathogenesis of schizophrenic disorders , we used an association study to genotype the P21554 REA polymorphism for 127 schizophrenic patients and 146 control subjects . The results demonstrate no association between P21554 REA genotypes and schizophrenic disorders ( P = 0.409 ) , with these negative findings suggesting that , for Chinese populations , the ( P01009 REA ) n triplet repeat in the promoter region of the P21554 REA gene is not directly involved in the pathogenesis of schizophrenic disorders .

Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia . Mutations in microsomal triglyceride transfer protein ( P55157 REA ) cause abetalipoproteinemia ( P00519 REA ) , characterized by the absence of plasma apoB-containing lipoproteins . In this study , we characterized the effects of various P55157 REA missense mutations found in P00519 REA patients with respect to their expression , subcellular location , and interaction with protein disulfide isomerase ( P07237 REA ) . In addition , we characterized functional properties by analyzing phospholipid and triglyceride transfer activities and studied their ability to support apoB secretion . All the mutants colocalized with calnexin and interacted with P07237 REA . We found that R540H and N780Y , known to be deficient in triglyceride transfer activity , also lacked phospholipid transfer activity . Novel mutants S590I and G746E did not transfer triglycerides and phospholipids and did not assist in apoB secretion . In contrast , D384A displayed both triglyceride and phospholipid transfer activities and supported apoB secretion . These studies point out that P00519 REA is associated with the absence of both triglyceride and phospholipid transfer activities in P55157 REA .