Attenuation of Cue-Controlled Cocaine-Seeking by a Selective D3 Dopamine Receptor Antagonist SB-277011-A

Conditioned stimuli (CS) previously paired with drugs of abuse can elicit cravings in humans, relapse to drug use, and can also reinforce drug-seeking behavior in both humans and animals, events that are believed to be subserved in part by activation of the mesolimbic dopamine system. Converging anatomical, pharmacological, and behavioral evidence implicates dopamine D3 receptors in the mechanisms underlying cue-controlled behaviors. The purpose of the present study was therefore to investigate the effects on cocaine-seeking behavior of a novel D3 receptor antagonist, SB-277011-A, which is 100-fold more selective for D3 over D2 dopamine receptors. We have established previously that second-order schedules of reinforcement provide an animal model of cue-controlled drug-seeking both prior to and after cocaine has been self-administered. SB-277011-A dose-dependently decreased cocaine-seeking maintained by a cocaine-associated conditioned reinforcer in both the first, drug-free interval and also following self-administration of cocaine. At higher doses, SB-277011-A also increased the latency to receive the first CS presentation and cocaine infusion, thereby decreasing the number of cocaine infusions self-administered under the second-order schedule of reinforcement. SB-277011-A had no effect on cocaine intake under an FR-1 schedule of reinforcement, or on responding for sucrose under a second-order schedule of reinforcement, at any dose tested. These results therefore suggest that D3 dopamine receptors may be critically involved in cue-controlled drug-seeking behavior independently of any interaction with the reinforcing effects of cocaine itself, and may therefore provide a therapeutic target in the treatment of relapse to cocaine use induced by CSs.