The role of central dopamine D3 receptors in drug addiction:: a review of pharmacological evidence

The cfYNA for the doparnine D-3 receptor was isolated and characterized in 1990. Subsequent studies have indicated that D3 receptors, as well as D-3 receptor mRNA, are primarily localized in limbic regions in mammals. This finding led to the postulate that D3 receptors may be involved in drug dependence and addiction. However, this hypothesis has been difficult to test due to the lack of compounds with high selectivity for central D-3 receptors. The interpretation of results from studies using mixed D-2/D-3 agonists and/or antagonists is problematic because these agents have low selectivity for D-3 over D-2 receptors and it is likely that their actions are primarily related to D-2 receptor antagonism and possibly interaction with other neurotransmitter receptors. Currently, with the synthesis and characterization of new highly selective D-3 receptor antagonists such as SB-277011-A this difficulty has been surmounted. The purpose of the present article is to review, for the first time, the effects of various putative D-3 receptor selective compounds in animal models of drug dependence and addiction. The results obtained with highly selective D-3 receptor antagonists such as SB-277011-A, SB-414796, and NGB-2904 indicate that central D-3 receptors may play an important role in drug-induced reward, drug-taking, and cue-, drug-, and stress-induced reinstatement of drug-seeking behavior. Provided these results can be extrapolated to human drug addicts, they suggest that selective DA D-3 receptor antagonists may prove effective as potential pharmacotherapeutic agents to manage drug dependence and addiction. (c) 2005 Elsevier B.V. All rights reserved.