During the period 01 Oct 09 to 30 Sept 10, significant progress was made on this research project. We found that blockade of brain dopamine D3 receptors by the novel preferential dopamine D3 receptor antagonist S33138 emulates the putative anti-addiction, anti-craving, and anti-relapse efects that we have previously seen with our lead proof-of-concept dopamine D3 receptor antagonist SB277011A. Specifically, we found that S33138 attenuates intravenous cocaine self-administration, attenuates relapse to cocaine-seeking behavior (using the reinstatement animal model) triggered by cocaine, and significantly attenuates drug-enhanced brain reward (as assessed by electrical brain-stimulation reward electrophysiological techniques) produced by cocaine. These effects were seen at low to moderate doses of S33138. At high doses, dopamine D2 antogonist-like effects were observed. These findings add further weight to our previous suggestions that selective dopamine D3 receptor antagonists may be useful in the treatment of drug addiction. With regard to the effects observed with high doses of S33138, we found them to be similar to those that we previously observed with the putative selective D3 antagonist BP897 - and we conclude that the effects of both S33138 and BP897 are likely attributable to a combination of D3 and D2 receptor antagonism. During the reporting period, we also studied the selective dopamine D3 receptor antagonist PG01037. We found that PG01037 shares a very similar profile of action in animal models of addiction as our lead compound SB277011A - PG01037 does not alter intravenous methamphetamine self-administration when the cocaine is available under low-effort high-payoff conditions, PG01037 significantly lowers the progressive-ratio breakpoint for intravenous methamphetamine self-administration under progressive-ratio reinforcement conditions (reflecting decreased incentive motivation to self-administer methamphetamine), PG01037 significantly inhibits methamphetamine-associated cue-triggered relapse to drug-seeking behavior in animals behaviorally extinguished and pharmacologically weaned from methamphetamine, and PG01037 significantly inhibits methamphetamine-enhanced brain stimulation reward. These findings suggest that dopamine D3 receptor antagonists may have anti-addiction, anti-craving, and anti-relapse efficacy in human drug addiction, and that the D3 antagonist PG01037 appears to possess the same anti-addiction profile observed with our lead proof-of-concept compounds SB277011A and NGB2904.
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