Pharmacology Of Dopamine Receptor Systems

National Institute On Drug Abuse

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Abstract

The roles of specific dopamine (DA) receptors in the behavioral effects of cocaine, including its psychomotor stimulant and subjective interoceptive, and reinforcing effects have been investigated. Using DA receptor knockout mice along with relatively selective DA antagonists we assessed the roles of dopamine receptors in various behavioral effects of cocaine. In studies of the locomotor stimulant effects, the prototypical partial agonist SKF 38393, produced limited changes in locomotor activity, whereas the partial agonists SKF 75670 and SKF 77434 produced locomotor stimulant effects that were similar to or greater than those of the full efficacy agonists SKF 82958 and SKF 81297. These results suggest that two second messenger systems may be differentially involved in the behavioral effects of D1-like agonists, and that the current classifications of D1-like agonists according to their intrinsic efficacies is in need of reexamination. We have recently completed a study of the effects of dopamine D2/3 antagonists on cocaine discrimination in dopamine D3 receptor KO and WT mice. In that study, the putative D3 partial agonist, BP897, and antagonists, NGB 2904 and nafadotride, were tested as antagonists of cocaine. BP897 significantly shifted the cocaine curve 3.51 and 1.47-fold to the right in WT and KO mice, respectively. In contrast, NGB 2904 significantly shifted the cocaine curve 2-fold to the left in WT mice, and had no significant effect on cocaine in KO mice. Both nafadotride, and the D2 selective antagonist, L 741,626, shifted the cocaine dose-effect curve to the right comparably in DA D3R KO and WT mice. The data indicate that activity of the D3 receptor is not essential for a discriminative effect of cocaine, as the effects were obtained in both lines of mice. However, BP897 antagonized the effect of cocaine in both lines of mice, but more so in WT subjects with intact D3 receptors, suggesting both D2 and D3 antagonist actions. In contrast, NGB 2904 differentially potentiated the effects of cocaine in WT mice, presumably via agonist actions at DA D3 receptors. The comparable effects of nafadotride and L 741,626 in the KO and WT mice suggests their antagonist effects were mediated by dopamine D2 receptors. This study suggests that drugs classified as DA D3R antagonists can have distinct pharmacological actions, and that care must be exercised in attributing their effects to antagonist actions at the DA D3R. It has been suggested that both BP897 and NGB2904 inhibit some of the reinforcing effects of cocaine. Our studies suggest radically different pharmacologies of these two drugs, and that without a pharmacological analysis of mechanism, it is premature to attributed the actions observed in various behavioral procedures as due to similar antagonist actions. Finally, the studies indicate that cocaine discrimination in DA D3R KO and WT mice can be used to determine the in vivo selectivity of the compounds.