Dopamine D3 receptor antagonists for treating drug addiction: Preclinical models

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During the period 01 Oct 06 to 30 Sept 07, major progress was made on this research project. We found that blockade of brain dopamine D3 receptors by the novel dopamine D3 receptor antagonist NGB2904 significantly attenuates cocaine-enhanced brain reward (as assessed by electrical brain-stimulation reward electrophysiological techniques), attenuates intravenous cocaine self-administration under progressive-ratio (PR) reinforcement (lowers the PR break-point), and attenuates cocaine-triggered relapse to drug-seeking behavior in the reinstatement animal model. Like the other selective D3 receptor antagonists that we have studied, NGB2904 does not alter cocaine self-administration under low-effort high-payoff fixed-ratio reinforcement. These findings add further weight to our previous suggestions that highly selective dopamine D3 receptor antagonists may be useful in the treatment of cocaine addiction. We further found that the D3 receptor antagonist SB277011A significantly attenuates nicotine-enhanced brain reward (as assessed by electrical brain-stimulation reward) and nicotine-paired environmental cue functions, using both the nicotine cue-paired locomotor activity and the nicotine cue-paired conditioned place preference behavioral paradigms. These findings constitute the first demonstration that dopamine D3 brain receptors are involved in nicotine dependence and addiction, and the first demonstration that highly selective dopamine D3 receptor antagonists may be therapeutically beneficial in the treatment of nicotine dependence and addiction. We further found that blockade of brain dopamine D3 receptors by SB277011A significantly attenuates oral alcohol self-administration and reinstatement of alcohol-seeking behavior in laboratory mice. These findings add further weight to our previous suggestions that highly selective dopamine D3 receptor antagonists may be useful in the treatment of alcohol dependence and addiction. We also found that blockade of brain dopamine D3 receptors by SB277011A significantly attenuates incubation of cocaine craving in laboratory rodents. This is the first demonstration of the potential efficacy of selective dopamine D3 receptor antagonists against not only craving itself, but the time-dependent incubation of craving that is such a problem in the clinical management of addictive diseases. We further found that the dopamine D3 receptor ligands SB277011A, NGB2904, and BP897 significantly attenuate methamphetamine-enhance brain-stimulation reward. We found that the anti-methamphetamine effects of SB277011A and NGB2904 are likely attributable to selective D3 receptor antagonism, while the observed effects of BP897 are likely attributable to a combination of D3 and D2 receptor antagonism. These findings constitute the first demonstration that dopamine D3 brain receptors are involved in methamphetamine dependence and addiction, and the first demonstration that highly selective dopamine D3 receptor antagonists may be therapeutically beneficial in the treatment of methamphetamine addiction. We also investigated the effects of the novel compound levo-tetrahydropalmatine (l-THP) on cocaine's rewarding effects. We found that l-THP significantly attenuates cocaine's rewarding effects as assessed by intravenous cocaine self-administration under both fixed-ratio and progressive-ratio reinforcement conditions, and as assessed by electrical brain-stimulation reward in laboratory animals. We further found that l-THP slightly enhances nucleus accumbens extracellular dopamine by itself (assayed by in vivo brain micordialysis), and strongly potentiates cocaine-augmented nucleus accumbens dopamine - suggesting that a postsynaptic, rather than presynaptic, dopamine receptor mechanism underlies l-THP's actions on cocaine reward. However, l-THP does not appear to be selective for the D3 receptor. Rather, it appears to act on dopamine D1, D2, and D3 receptors in a nonselective manner. Finally, we found that the dopamine D3 receptor antagonist SB277011A significantly inhibits food intake in genetically obese rodents, with significantly lesser effect on genetically non-obese rodents - suggesting a possible utility for selective dopamine D3 receptor antagonists in the treatment of compulsive over-eating and obesity. All of these findings suggest that dopamine D3 receptor antagonists may have anti-addiction, anti-craving, and anti-relapse efficacy in human drug addiction, with additional preliminary suggestive evidence for efficacy in compulsive over-eating and obesity.