SR141716, a central cannabinoid (CB(1)) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats.
The central CB(1) cannabinoid receptor has recently been implicated in brain reward function. In the present study we evaluated first the effects of the selective CB(1) receptor antagonist, SR141716, on the motivational effects of nicotine in the rat. Administration of SR141716 (0.3 and 1 mg/kg) decreased nicotine self-administration (0.03 mg/kg/injection). SR141716 (0.3-3 mg/kg) neither substituted for nicotine nor antagonized the nicotine cue in a nicotine discrimination procedure, but dose-dependently (0.01-1 mg/kg) antagonized the substitution of nicotine for D-amphetamine, in rats trained to discriminate D-amphetamine. Secondly, using brain microdialysis, SR141716 (1-3 mg/kg) blocked nicotine-induced dopamine release in the shell of the nucleus accumbens (NAc) and the bed nucleus of the stria terminalis. To investigate whether SR141716 would block the dopamine-releasing effects of another drug of abuse, we extended the neurochemical study to the effect of ethanol, consumption of which in rodents is reduced by SR141716. Dopamine release induced by ethanol in the NAc was also reduced by SR141716 (3 mg/kg). These results suggest that activation of the endogenous cannabinoid system may participate in the motivational and dopamine-releasing effects of nicotine and ethanol. Thus, SR141716 may be effective in reduction of alcohol consumption, as previously suggested, and as an aid for smoking cessation.
Cohen
C
C
Sanofi-Synthélabo, Bagneux, France. Caroline.cohen@sanofi-synthelabo.com
Perrault
G
G
Voltz
C
C
Steinberg
R
R
Soubrié
P
P
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002492:Central Nervous System Depressants / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D009042:Motivation; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors*; D012054:Reinforcement, Psychology; D000077285:Rimonabant; D012646:Self Administration
D002492:Central Nervous System Depressants; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D000431:Ethanol; D009538:Nicotine; D000077285:Rimonabant; D004298:Dopamine