Studies have been conducted to better document the behavioral pharmacology of drugs acting on dopaminergic systems. These studies have examined specific D1, D2, and D3 dopamine receptor agonists and antagonists. The overall goal of these studies is to better characterize the behavioral pharmacology of drugs acting on these systems and the mechanisms responsible for those behavioral effects. These studies indicate that: (1) some of the D2 agonists can stimulate behavior in a manner similar to cocaine, suggesting that the stimulant effects of cocaine are due to actions mediated through D2 receptors. However, some of the D2 agonists do not have effects that are equivalent to cocaine. An in vitro assay of intrinsic efficacy is being established in order to determine if the differences among these drugs are due to differences in intrinsic efficacy. There currently are no assays available to provide that information. (2) the D1 agonist, SKF 38393, is not well antagonized by D1 antagonists, whereas other D1 agonists are. These results indicate that much of the behavioral effects often attributed to D1 agonist activity of SKF 38393 are likely a result of activation of other mechanisms. Several biochemical studies are being initiated to better understand the actions of D1 agonsits. (3) D2 agonists produce a unique scratching behavior in primates. This effect of these agonists appears to be pharmacologically specific (drugs acting by other mechanisms generally do not produce this effect). Recently, we observed that the D3 agonist, 7-OH-DPAT, also produces this effect, and experiments are being conducted to determine whether the effect of 7-OH-DPAT is being mediated by D2 or D3 receptors. This effect could serve as a good in vivo assay of D2 receptor activity and will be useful in documenting the D2 agonist activity of novel compounds. In addition, it may be used to characterize the D2 agonist sensitivity of primates with various exposures to cocaine, or those that may be acutely sensitive to the effects of drugs of abuse. (4) Biochemical studies have indicated that the D1 receptor in rodents and primates may be significantly different. These results suggest that there has been a phylogeny of the D1 receptor, and that the effects of drugs acting at this receptor in man may not be predictable from studies in rodents.
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