Dopamine D3 receptor antagonists-treating drug addiction

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During the period 01 Oct 04 to 30 Sept 05, major progress was made on this research project. We found that blockade of brain dopamine D3 receptors by the D3 receptor antagonist SB277011A significantly attenuates stress-triggered relapse to cocaine-seeking behavior in laboratory rats who had been pharmacologically detoxified and behaviorally extinguished from their prior intravenous cocaine-taking habits. By microinjecting the D3 receptor antagonist directly into the brain, we found that one brain site of anti-relapse action is the nucleus accumbens. We further found that blockade of brain dopamine D3 receptors by the D3 receptor antagonists SB277011A, NGB2904, or BP897 significantly attenuates relapse to cocaine-seeking behavior in laboratory rats triggered by exposure to environmental cues previously associated with the intravenous cocaine-taking habit. We further determined that the anti-relapse actions of SB277011A and NGB2904 were likely due to their D3 receptor antagonist properties, but that the anti-relapse action of BP897 was likely due to D2 receptor antagonist properties. We further determined that the D3 receptor antagonist SB277011A blocks alcohol consumption in both genetically alcohol-preferring and alcohol-nonpreferring laboratory rats. We further determined that the D3 receptor antagonist SB277011A significantly attenuates cocaine-induced reward in laboratory rats by two different preclinical procedures--progressive-ratio reinforcement and variable-cost/variable-payoff reinforcement. We further determined that the D3 receptor antagonists SB277011A, NGB2904, or BP897 significantly attenuate nicotine-induced enhancement of brain reward. All of these findings suggest that dopamine D3 receptor antagonists may have anti-addiction, anti-craving, and anti-relapse efficacy in human drug addiction.