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

Abstract

The cDNA for the dopamine D3 receptor was isolated and characterized in 1990. Subsequent studies have indicated that D3 receptors, as well as D3 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 D3 receptors. The interpretation of results from studies using mixed D2/D3 agonists and/or antagonists is problematic because these agents have low selectivity for D3 over D2 receptors and it is likely that their actions are primarily related to D2 receptor antagonism and possibly interaction with other neurotransmitter receptors. Currently, with the synthesis and characterization of new highly selective D3 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 D3 receptor selective compounds in animal models of drug dependence and addiction. The results obtained with highly selective D3 receptor antagonists such as SB-277011-A, SB-414796, and NGB-2904 indicate that central D3 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 D3 receptor antagonists may prove effective as potential pharmacotherapeutic agents to manage drug dependence and addiction.

Fig. 1

Distribution of D₃ receptors in rat brain, as revealed by [³H]-7-OH-DPAT autoradiography—displacement with the selective DA D₃ receptor antagonist SB-277011. Coronal rat brain sections (at +1.70 mm from Bregma) were incubated in the presence of 0.5 nM [³H]7-OH-DPAT for 60 min at room temperature. (A) Total binding; (B) nonspecific binding, in the presence of 1 µM dopamine; (C) binding in the presence of 100 nM SB-277011-A; (D) binding in the presence of 1 µM SB-277011-A. Calibration bars correspond to 2 mm. Incubation with [³H]-7-OH-DPAT was performed in the presence of 1 mM EDTA, in order to abolish the radioligand binding to D₂ receptors without affecting that to D₃ receptors, as demonstrated in transfected cell lines [182]. The specificity of the radioligand binding to D₃ receptors was confirmed by the distribution of [³H]-7-OH-DPAT binding sites, in line with that of D₃ mRNA [30] and by displacement with the selective D₃ antagonist SB-277011-A. As predicted by the affinity values of [³H]7-OH-DPAT and SB-277011-A for rat D₂ and D₃ receptors [182,229], 0.5 nM [³H]7-OH-DPAT binding was inhibited by 80% and 100% by 100 nM and 1 µM SB-277011-A, respectively.