Selective antagonism at dopamine D3 receptors attenuates cocaine-seeking behaviour in the rat

Dopamine (DA) D₃ receptors have been suggested to play a role in mechanisms underlying the ability of drug-associated cues to induce drug-seeking behaviour. The present study investigated whether SB-277011-A, a selective DA D₃ receptor antagonist, modulates reinstatement of cocaine-seeking behaviour induced by cocaine-associated stimuli. The study also explored whether or not this modulation is generable to seeking behaviours associated with a nutritive reinforcer such as sucrose. Separate groups of rats were trained to associate discriminative stimuli (S^D) with the availability of cocaine or sucrose pellets vs. non-reward under a FR1 schedule of reinforcement. Each reinforced response was followed by a response-cue signalling a 20-s time-out (TO). After the self-administration training criterion was met, rats underwent extinction during which cocaine, sucrose pellets and S^Ds were withheld. Reinstatement tests, separated by 3 d during which rates of responding under extinction conditions remained at the criterion, were performed by presenting S^Ds non-contingently together with the contingent presentation of response-cues signalling a 20-s TO. Within- and between-subjects experimental designs revealed that 10 and 30 mg/kg SB-277011-A attenuated reinstatement of cocaine-seeking. SB-277011-A (10 mg/kg) did not modify conditioned reinstatement triggered by sucrose pellet-associated cues. These results, provided they can be extrapolated to abstinent human addicts, suggest the potential therapeutic use of selective DA D₃ receptor antagonists for the prevention of cue-controlled cocaine-seeking and relapse.