The dopaminergic system is clearly implicated as important in mediating the effects of many drugs of abuse, as well as Parkinsons disease, and schizophrenia. Our studies have as their goals the determination of the functional significance of the dopamine system in normal functioning, as well as how it acts to subserve drug abuse. One specific objective is to better characterize the pharmacology of the various subtypes of CNS dopamine receptors. Included in this goal is the identification of drugs that act selectively and with high efficacy. In many cases the pharmacological tools for the study of these receptor subtypes in vivo and in vitro are limited. As a result, one further goal is the discovery of new synthetic entities that will allow analysis of the pharmacology of these dopamine receptor subtypes. These studies have indicated that: (1) Many of the known dopamine D2 agonists also have affinity for dopamine D3 receptors. Studies are being conducted in order to discover drugs that are selective for either D2 or D3 receptors. Recent studies have focused on the putative D3 receptor agonists 7-OH-DPAT, quinpirole, and PD 128,907. These three preferential D3 agonists produced subjective effects that were similar, based on their interchangeability in rats trained to discriminate these drugs from saline injections. In addition, the pharmacology of each of these drugs was similar to the others based on the spectrum of compounds that exhibited pharmacological equivalence. Most important, the selective D2 agonist, U91356A, fully substituted for both PD 128,907 and 7-OH-DPAT. This result suggests that the subjective effects of these D3 agonists were mediated by actions at D2 dopamine receptors. This result may be related to the relatively lower level of D3 receptors in the CNS compared to D2 receptors. Currently, there is no known function for this class of dopamine receptors. Interestingly, cocaine failed to substitute for either 7-OH-DPAT or PD 128,907, suggesting that the complexity of actions of cocaine render its subjective effects substantially different from those of direct acting agonists. - Dopamine, mechanisms, behavior
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