Dopamine D3 receptor antagonists for treating drug addiction: Preclinical models

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During the period 01 Oct 07 to 30 Sept 08, significant progress was made on this research project. We found that blockade of brain dopamine D3 receptors by the novel dopamine D3 receptor antagonist NGB2904 emulates to a very high degree 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 NGB2904 attenuates intravenous cocaine self-administration under progressive-ratio (PR) reinforcement (lowers the PR break-point), attenuates relapse to cocaine-seeking behavior (using the reinstatement animal model) triggered by both cocaine itself and by environmental cues (sights, sounds) that were previously associated with cocaine-taking behavior, and significantly attenuates drug-enhanced brain reward (as assessed by electrical brain-stimulation reward electrophysiological techniques) produced by cocaine, nicotine, and heroin. 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. Like SB277011A, NGB2904 has no effect by itself on electrical brain-stimulation reward - a highly promising finding with respect to possible eventual human use of these candidate anti-addiction medications. These findings add further weight to our previous suggestions that highly selective dopamine D3 receptor antagonists may be useful in the treatment of a wide range of drug addictions. We further found that both of our highly-selective D3 receptor antagonists - SB277011A and NGB2904 - significantly attenuate methamphetamine-enhanced brain reward (as assessed by electrical brain-stimulation reward). This finding constitutes 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 dependence and addiction. We further compared the effects of SB277011A and NGB2904 with those of BP897 against methamphetamine-enhanced brain reward, and concluded 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. We continued our investigation of the anti-addiction effects of SB277011A in an oral ethanol self-administration model, and confirmed our previous findings that SB277011A significantly attenuates ethanol self-administration and reinstatement of ethanol-seeking behavior in laboratory mice. We continued our investigation of the novel anti-addiction compound levo-tetrahydropalmatine (l-THP) on cocaine's rewarding effects, and confirmed that l-THP significantly attenuates cocaine self-administration and cocaine-enhanced brain-stimulation reward. In a series of neurochemical experiments, we found that l-THP likely works via a postsynaptic mechanism, and appears to antagonize dopamine D1, D2, and D3 receptors nonselectively. Additionally, we 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. 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.