During the period 01 Oct 05 to 30 Sept 06, 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 nicotine-enhanced brain reward, as assessed by electrical brain-stimulation reward electrophysiological techniques. We further found that the D3 receptor antagonist SB277011A significantly attenuates 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 the enhanced brain reward produced by delta-9-tetrahydrocannabinol, the psychoactive and addictive constitutent of marijuana and hashish. In addition, we found that blockade of brain dopamine D3 receptors by SB277011A significantly attenuates the enhanced extracellular levels of the brain neurotransmitter dopamine produced by delta-9-tetrahydrocannabinol in the reward-related nucleus accumbens of the brain. These findings constitute the first demonstration that dopamine D3 brain receptors are involved in marijuana dependence and addiction, and the first demonstration that highly selective dopamine D3 receptor antagonists may be therapeutically beneficial in the treatment of marijuana dependence and addiction. We further found that blockade of brain dopamine D3 receptors by SB277011A significantly attenuates alcohol self-administration in laboratory rodents, and also significantly attenuates relapse to alcohol-seeking behavior in laboratory rodents behaviorally extinguished and pharmacologically detoxified from their previous alcohol-taking habits. Coupled with the findings that we reported last year on the involvement of dopamine D3 brain receptors in alcohol-seeking behavior, these data constitute the first demonstration that dopamine D3 brain receptors are involved in alcohol dependence and addiction, and the first demonstration that highly selective dopamine D3 receptor antagonists may be therapeutically beneficial in the treatment of alcohol dependence and addiction. Finally, we found that the chemically novel dopamine D3 receptor antagonist NGB2904 significantly inhibits cocaine's brain reward-enhancing effects and also significantly inhibits drug-triggered relapse to cocaine-seeking behavior in laboratory rodents behaviorally extinguished and pharmacologically detoxified from their previous cocaine-taking habits. Coupled with findings that we reported in previous years, these data add impressively to the evidence that dopamine D3 brain receptors are involved in cocaine addiction, and that highly selective dopamine D3 receptor antagonists may be therapeutically beneficial in the treatment of cocaine dependence and addiction. The findings with the chemically novel compound NGB2904 are especially important, in that they strongly suggest that our previous findings with SB277011A are attributable to SB277011A's dopamine D3 receptor antagonist properties rather than to some other idiosyncratic pharmacological property of SB277011A. We further determined that the anti-relapse actions of SB277011A and NGB2904 are likely due to their D3 receptor antagonist properties, but that the anti-relapse action of BP897 is likely due to D2 receptor antagonist properties. All of these findings suggest that dopamine D3 receptor antagonists may have anti-addiction, anti-craving, and anti-relapse efficacy in human drug addiction.
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