Effect of the cannabinoid CB1 receptor antagonist SR-141716A on ethanol self-administration and ethanol-seeking behaviour in rats.
BACKGROUND
It has been suggested that endocannabinoid mechanisms are involved in the control of ethanol consumption.


OBJECTIVE
The aims of the present study were (1) to evaluate the role of the endocannabinoid system in the control of operant ethanol self-administration and in the reinstatement of ethanol seeking, when induced by stress or conditioned stimuli and (2) to offer new insights on the specificity of such a role.


METHODS
Rats were administered intraperitoneally with the selective cannabinoid CB1 receptor antagonist, SR-141716A, 30 min before operant self-administration or reinstatement sessions. Two schedules of reinforcement, the fixed-ratio 1 (FR1) and the progressive ratio (PR), were used to study 10% (w/v) alcohol and 5.0% sucrose self-administration. NaCl (2% w/v) intake in sodium-depleted rats was studied only under the FR1 program.


RESULTS
Treatment with SR-141716A (0.3-3.0 mg/kg) significantly attenuated FR1 alcohol self-administration and lowered the break point for ethanol under PR. SR-141716A also markedly inhibited the reinstatement of alcohol seeking elicited by presentation of cues predictive of drug availability. Conversely, the cannabinoid antagonist did not prevent the reinstatement of alcohol seeking induced by foot-shock stress. Lever pressing for sucrose under FR1 and PR schedules was also significantly decreased by SR-141716A treatment, whereas the drug modestly and only at the highest dose decreased 2% NaCl self-administration.


CONCLUSIONS
Results emphasize that endocannabinoid mechanisms play a major role in the control of ethanol self-administration and in the reinstatement of conditioned ethanol seeking. However, these effects extend to the control of operant behaviours motivated by natural rewards (i.e. sucrose). On the other hand, SR-141716A only weakly reduces NaCl self-administration in sodium-depleted rats, in which salt intake is largely controlled by homeostatic mechanisms. Overall, these observations demonstrate that the inhibition of operant behaviour following blockade of CB1 receptors by SR-141716A is linked to a reduction of reward-related responding and is not related to drug-induced motor deficits.
Economidou
Daina
D
Department of Experimental Medicine and Public Health, University of Camerino, Via Scalzino 3, 62032, Camerino, Italy.
Mattioli
Laura
L
Cifani
Carlo
C
Perfumi
Marina
M
Massi
Maurizio
M
Cuomo
Vincenzo
V
Trabace
Luigia
L
Ciccocioppo
Roberto
R
D000428:Alcohol Drinking / Q000188:drug therapy* / Q000523:psychology; D000818:Animals; D002492:Central Nervous System Depressants / Q000097:blood; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D004597:Electroshock; D000431:Ethanol / Q000097:blood; D005108:Extinction, Psychological / Q000187:drug effects; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D012055:Reinforcement Schedule; D000077285:Rimonabant; D012646:Self Administration; D012965:Sodium Chloride / Q000494:pharmacology; D013395:Sucrose / Q000494:pharmacology
D002492:Central Nervous System Depressants; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000431:Ethanol; D012965:Sodium Chloride; D013395:Sucrose; D000077285:Rimonabant