Evaluation of the role of nicotinic acetylcholine receptor subtypes and cannabinoid system in the discriminative stimulus effects of nicotine in rats

Abstract

Male Wistar rats were trained to discriminate (−)-nicotine (0.4 mg/kg) from saline under a two-lever, fixed-ratio 10 schedule of water reinforcement. During test sessions the following drugs were coadministered with saline (substitution studies) or nicotine (0.025–0.4 mg/kg; combination studies): the α 4β 2 nicotinic acetylcholine receptor subtype antagonist dihydro-β-erythroidine (DHβE), the non-selective nicotinic acetylcholine receptor subtype antagonist mecamylamine, the α 7 nicotinic acetylcholine receptor subtype antagonist methyllycaconitine (MLA), the α 4β 2 nicotinic acetylcholine receptor subtype agonist 5-iodo-3-(2( S)-azetidinylmethoxy)pyridine (5-IA), the cannabinoid CB 1 receptor antagonist/partial agonist rimonabant, the cannabinoid CB 2 receptor antagonist N-[(1 S)-endo-1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl]5-(4-chloro-3-methyl-phenyl)-1-(4-methybenzyl)pyrazole-3-carboxamide (SR 144528), the cannabinoid CB 1/2 receptor agonists (−)- cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]- trans-4-(3-hydroxy-propyl)cyclohexanol (CP 55,940) or R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]-pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-(1-naphthalenyl)-methanone mesylate (WIN 55,212-2), the endogenous cannabinoid agonist and non-competitive α 7 nicotinic acetylcholine receptor subtype antagonist anandamide, the anandamide uptake and fatty acid amide hydrolase inhibitor N-(4-hydroxyphenyl)-5 Z,8 Z,11 Z,14 Z-eicosatetraenamide (AM-404), the fatty acid amide hydrolase inhibitor cyclohexylcarbamic acid 3′-carbamoyl-biphenyl-3-yl ester (URB 597), AM-404 + anandamide or URB 597 + anandamide. 5-IA (0.01 mg/kg) fully substituted for nicotine, while other drugs were inactive. In combination studies, DHβE and mecamylamine dose-dependently attenuated the discriminative stimulus effects of nicotine and the full substitution of 5-IA, while MLA, rimonabant, SR 144528, CP 55,940, WIN 55,212-2, and URB 597 did not alter the nicotine cue. Pretreatment with AM-404 + anandamide or URB 597 + anandamide weakly enhanced nicotine-lever responding. Our pharmacological analyses demonstrates that the expression of nicotine discrimination is under the control of nicotinic acetylcholine receptor subtypes composed of α 4β 2 (but not of α 7) subunits. Furthermore, we excluded the involvement of either cannabinoid CB 1 and CB 2 receptors or increases in the endocannabinoid tone in the nicotine discrimination.