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Role of CB2 cannabinoid receptors in the rewarding, reinforcing, and physical effects of nicotine.

ABSTRACT: This study was aimed to evaluate the involvement of CB2 cannabinoid receptors (CB2r) in the rewarding, reinforcing and motivational effects of nicotine. Conditioned place preference (CPP) and intravenous self-administration experiments were carried out in knockout mice lacking CB2r (CB2KO) and wild-type (WT) littermates treated with the CB2r antagonist AM630 (1 and 3?mg/kg). Gene expression analyses of tyrosine hydroxylase (TH) and ?3- and ?4-nicotinic acetylcholine receptor subunits (nAChRs) in the ventral tegmental area (VTA) and immunohistochemical studies to elucidate whether CB2r colocalized with ?3- and ?4-nAChRs in the nucleus accumbens and VTA were performed. Mecamylamine-precipitated withdrawal syndrome after chronic nicotine exposure was evaluated in CB2KO mice and WT mice treated with AM630 (1 and 3?mg/kg). CB2KO mice did not show nicotine-induced place conditioning and self-administered significantly less nicotine. In addition, AM630 was able to block (3?mg/kg) nicotine-induced CPP and reduce (1 and 3?mg/kg) nicotine self-administration. Under baseline conditions, TH, ?3-nAChR, and ?4-nAChR mRNA levels in the VTA of CB2KO mice were significantly lower compared with WT mice. Confocal microscopy images revealed that CB2r colocalized with ?3- and ?4-nAChRs. Somatic signs of nicotine withdrawal (rearings, groomings, scratches, teeth chattering, and body tremors) increased significantly in WT but were absent in CB2KO mice. Interestingly, the administration of AM630 blocked the nicotine withdrawal syndrome and failed to alter basal behavior in saline-treated WT mice. These results suggest that CB2r play a relevant role in the rewarding, reinforcing, and motivational effects of nicotine. Pharmacological manipulation of this receptor deserves further consideration as a potential new valuable target for the treatment of nicotine dependence.

SUBMITTER: Navarrete F

PROVIDER: S-EPMC3799072 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Role of CB2 cannabinoid receptors in the rewarding, reinforcing, and physical effects of nicotine.

Navarrete Francisco F Rodríguez-Arias Marta M Martín-García Elena E Navarro Daniela D García-Gutiérrez María S MS Aguilar María A MA Aracil-Fernández Auxiliadora A Berbel Pere P Miñarro José J Maldonado Rafael R Manzanares Jorge J Manzanares Jorge J

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20130702 12

This study was aimed to evaluate the involvement of CB2 cannabinoid receptors (CB2r) in the rewarding, reinforcing and motivational effects of nicotine. Conditioned place preference (CPP) and intravenous self-administration experiments were carried out in knockout mice lacking CB2r (CB2KO) and wild-type (WT) littermates treated with the CB2r antagonist AM630 (1 and 3 mg/kg). Gene expression analyses of tyrosine hydroxylase (TH) and α3- and α4-nicotinic acetylcholine receptor subunits (nAChRs) in ...[more]

PMID: 23817165

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Project description:Background and purposeCannabinoid-2 (CB(2)) receptor-selective agonists have shown anti-nociceptive activity in models of neuropathic and inflammatory pain, and the two agonists most widely used, (+/-)AM1241 [(2-iodo-5-nitrophenyl)-[1-(1-methylpiperidin-2-ylmethyl)-1H-indol-3-yl-methanone] and L768242 [(2,3-dichloro-phenyl)-[5-methoxy-2-methyl-3-(2-morpholin-4-yl-ethyl)-indol-1-yl]-methanone] (GW405833), have been suggested to be protean agonists. Here we investigated the role of the constitutive activity of CB(2) receptors in (+)AM1241 and L768242 protean agonism.Experimental approachPharmacological profiles of CB(2) receptor ligands were evaluated in Chinese hamster ovary cells expressing recombinant human (hCB(2)) or rat (rCB(2)) receptors, by measuring modulation of cAMP. To assess the influence of constitutive activity on pharmacological profile, constitutive activity was abolished by pretreatment with AM630 [(6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl) methanone)], followed by extensive washing.Key resultsIn cell lines expressing either hCB(2) or rCB(2) receptors, (+)AM1241 did not reverse forskolin stimulation of cAMP levels. Conversely, L768242 was an inverse agonist at both hCB(2) and rCB(2) receptors. Abolition of constitutive activity disclosed (+)AM1241 and L768242 agonist activity, while activity of CP55940 [5-(1,1-dimethylheptyl)-2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol] was unaffected and AM630 became a neutral antagonist. In presence of constitutively active CB(2) receptors, (+)AM1241 antagonized CP55940, but when constitutive activity was abolished, it acted as a partial agonist with additive or antagonistic behaviour, depending on concentration.Conclusions and implicationsThese results show that (+)AM1241 and L768242 are protean agonists at both hCB(2) and rCB(2) receptors. Abolition of constitutive activity reveals the agonist activity of these compounds. Thus, differences between in vivo and in vitro profiles of CB(2) receptor agonists could be due to different levels of constitutive activity in recombinant versus native CB(2) receptors.

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Role of CB2 cannabinoid receptors in the rewarding, reinforcing, and physical effects of nicotine.

Publications

Role of CB2 cannabinoid receptors in the rewarding, reinforcing, and physical effects of nicotine.

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