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. Several studies have focused on the DA D3 receptor as a critical target for the development of treatments for cocaine abuse. Unfortunately, at this time there are no validated in vivo techniques for determining efficacy of putative DA D3 ligands, nor for that matter are there studies that clearly differentiate compounds as having selective DA D3 actions in vivo. Moreover, there is no clear evidence of the importance of DA D3 mediated actions in the behavioral effects of cocaine. DA D3R KO mice and their WT littermates were trained to discriminate injections of cocaine from saline. Pressing one lever was intermittently reinforced after injection of cocaine and the other lever after injection of saline. The putative selective DA D3R agonists (7-OH-DPAT, PD 128,907, and quinpirole) were examined for their effectiveness in substituting for cocaine, and in decreasing the rate at which the mice pressed the lever. None of the drugs fully substituted for cocaine, except occasionally at the highest doses tested which profoundly decreased response rates. With quinpirole, and only with quinpirole, there was a clear difference in potency of the drug for its effects on rate of responding. WT mice were approximately 3- to 10-fold more sensitive to the effects of quinpirole than were the KO littermates. Thus with this agonist, and only this agonist, there was evidence for an in vivo effect on DA D3 receptors. However, because this DA D3 agonist did not substitute for cocaine, the data suggest that the DA D3 receptor plays a minimal role in the discriminative stimulus effects of cocaine. Putative DA D3R antagonists (nafadotride, BP 897, and NGB 2904) were examined for their effectiveness as antagonists of cocaine in mice trained to discriminate cocaine from saline. NGB 2904 did not antagonize cocaine. Rather this compound potentiated the effects of cocaine in WT but not KO mice. These data suggest that NGB 2904 is a DA D3R agonist rather than antagonist. Nafadotride was effective as an antagonist of cocaine, shifting the cocaine dose-effect curve to the right. This antagonist effect was present in both WT and KO mice, indicating that the antagonism of cocaine by nafadotride is not mediated by DA D3 receptors. In contrast to the other putative antagonists, BP 897 clearly antagonized the effects of cocaine, and did so more potently in DA D3R WT mice compared to KO mice. These results indicate that among the antagonists examined, only BP 897 has D3R antagonist actions in vivo. That a DA D3R antagonist shifted the cocaine dose-effect curve to the right is surprising when considered along with the findings that DA D3R agonists did not substitute for cocaine. Studies to reconcile these findings are currently in progress. The dopamine D1-like receptor agonists have traditionally been defined molecularly by their efficacy in stimulating cyclic AMP accumulation. However, evidence correlating the effectiveness of these drugs in functional assays and their effectiveness biochemically has not been forthcoming. As a consequence, mechanism of action for the behavioral effects of D1-like agonists remains uncertain. The present study compared the locomotor stimulant effects among a series of D1-like agonists with different efficacies in stimulating AC. Rats were injected and immediately placed in the locomotor activity chamber for a period of 90 min. The rank order of maximal stimulation of locomotor activity did not agree with the rank order of efficacy of these compounds in stimulating cyclic AMP.Several ?full agonists,? bbased on stimulation of cyclic AMP, were less effective in stimulating locomotor activity than were several partial agonists. The present results suggest that effects other than those mediated by stimulation of AC formation may play an important role in the behavioral effects of dopamine D1-like agonists. Because these agents may be useful in treating cocaine abuse, an adequate description of their mechanism of action will help in the discovery of new treatments for cocaine abuse.