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 PD 128,907 and quinelorane. Each of these preferential D3 agonists produced subjective effects similar, but not identical to those of cocaine, as indicated by their substitution for cocaine in a drug discrimination procedure. In contrast, the selective D2 agonist, U91356A, produced a relatively lower level of substitution for cocaine. These data suggest that the subjective effects of cocaine are more closely related to actions mediated by D3 dopamine receptors than by actions mediated by D2 receptors. One hypothesis implied from these findings is that D3 dopamine receptors may be, more than D2 dopamine receptors, critical components of the biological substrates of reward mechanisms in the brain. (2) Novel dopamine D4 receptor antagonists have been examined behaviorally. Surprisingly, none of the D4 antagonists studied to date have behavioral effects. These studies contrast with the potent activity of D1 and D2 antagonists. The activity of these latter antagonists suggests that significant dopaminergic tone at D1 and D2 receptors is interrupted by these antagonists, leading to their behavioral activity. The lack of activity of D4 dopamine receptor antagonists suggests an absence of dopaminergic tone at D4 dopamine receptors.
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