SR141716, a central cannabinoid (CB1) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats

Abstract

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.

Nicotine-Associated Cues Maintain Nicotine-Seeking Behavior in Rats Several Weeks after Nicotine Withdrawal: Reversal by the Cannabinoid (CB1) Receptor Antagonist, Rimonabant (SR141716)

“…), reduced nicotine self-administration in rats (Cohen et al, 2002). Here, we report that rimonabant (1 mg/kg, i.p.)…”

“…In a previous study, we have identified mesolimbic dopaminergic transmission as a possible neurochemical substrate of rimonabant-induced reduction of nicotine selfadministration (Cohen et al, 2002). Indeed, rimonabant reduced the dopamine-releasing effects of nicotine as assessed by brain microdialysis and drug discrimination.…”

“…It is possible that nicotine-associated cues stimulate dopamine neurotransmission in specific brain regions as it was shown for cocaine-associated cues (Ito et al, 2000(Ito et al, , 2002Phillips et al, 2003). Rimonabant might prevent such activation and/ or its effects on postsynaptic transmission (Cohen et al, 2002).…”

“…Acquisition of self-administration was performed as described previously with slight modifications (Cohen et al, 2002(Cohen et al, , 2003.…”

“…Pretreatment with the cannabinoid CB 1 receptor antagonist rimonabant (SR141716; Rinaldi-Carmona et al, 1994) reduced nicotine, ethanol, methamphetamine, and morphine self-administration in rodents (Arnone et al, 1997;Navarro et al, 2001;Cohen et al, 2002;Vinklerova et al, 2002). Rimonabant also blocked the acquisition of conditioned place preference induced by morphine and cocaine (Chaperon et al, 1998).…”