During the present reporting period, significant progress was made on this research project. We found that blockade of brain dopamine D3 receptors by our lead proof-of-concept dopamine D3 receptor antagonist SB277011A inhibits methamphetamine self-administration and methamphetamine-triggered reinstatement of drug-seeking behavior in laboratory rats. This constitutes a major advance in the field, as methamphetamine is a major drug of abuse against which very few putative anti-addiction pharmacotherapies have shown any positive effects in animal models of addiction. During this 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 that the D3 antagonist PG01037 appears to possess the same anti-addiction profile observed with our lead proof-of-concept compounds SB277011A and NGB2904. This is an important finding because, as noted above, methamphetamine has to date proven to be remarkably resistant to previous putative anti-addiction pharmacotherapies. Also during the present reporting period, we started studying the novel selective dopamine D3 receptor antagonist YQA14. We found that YQA14 inhibits intravenous cocaine self-administration under fixed-ratio reinforcement in laboratory rats, and also significantly attenuates intravenous cocaine self-administration under progressive-ratio reinforcement in laboratory rats - revealing a significant decrease in incentive motivation to self-administer cocaine. At the same time, YQA14 does not alter self-administration of the natural rewarding substance sucrose. This is in line with our previous findings with our two lead proof-of-concept compounds SB277011A and NGB2904 that selective dopamine D3 receptor antagonism blocks drug reward but not natural biologically essential rewards such as food, water, or sex. In addition, we found that YQA14 does not alter cocaine-enhanced locomotion at doses that significantly inhibit cocaine self-administration, showing that YQA14's anti-cocaine effect is not merely due to nonspecific inhibition of motoric ability. In addition, we found that YQA14 dose-dependently inhibits intravenous cocaine self-administration (under both fixed-ratio and progressive-ratio reinforcement conditions) in wild-type mice but not in dopamine D3 receptor gene-deleted mice. This shows that the anti-addiction effects of YQA14 are indeed mediated via the dopamine D3 receptor in the brain. Thus, YQA14 now joins SB277011A and NGB2904 as an extremely promising anti-addiction medication, adding yet more weight to our previous findings that selective dopamine D3 receptor antagonists appear to have anti-addiction, anti-craving, and anti-relapse efficacy that may well translate to clinical efficacy in human drug addiction. Using two new additional animal behavioral models, we further found that our lead proof-of-concept compound SB277011A reverses conditioned place aversion produced by naloxone-precipitated opiate withdrawal in rats - suggesting efficacy of selective dopamine D3 receptor antagonists for treating opiate withdrawal dysphoria. And we found that SB277011A very robustly inhibits incubation of cocaine craving in laboratory rats, with locus of action in the brain being the nucleus accumbens and central amygdala (as determined by discrete focal intracerebral microinjections of SB277011A) - suggesting potential efficacy of selective dopamine D3 antagonists for treating time-dependent incubation of psychostimulant craving in human addicts. These two most recent findings significantly broaden the range of pathognomonic symptoms of drug addiction against which selective dopamine D3 antagonists show efficacy - a very important development in this research field.
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