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, the D2-like (D2, D3, and D4) and D1-like (D1 and D5) dopamine receptors. Studies have indicated that the psychomotor stimulant effects of cocaine, as indicated by increases in locomotor activity, may be mediated by D1-like and D2-like dopamine receptors. Pharmacological studies with selective antagonists indicate that neither D3 nor D4 dopamine receptors, which are both subtypes within the D2-like category, are involved in the locomotor stimulant effects of cocaine. Studies of D2 dopamine receptor knockout mice suggest that the stimulant effects of cocaine are reduced in potency and efficacy in these animals. Studies of D5 dopamine receptor knockout mice suggest a minimal role of these receptors in mediating the stimulant effects of cocaine. These studies together suggest an additional role for D1 dopamine receptors in the residual stimulant effects occurring in D2 KO mice. The subjective behavioral effects of cocaine are mediated by both D1- and D2-like dopamine receptor systems. Studies with D2 dopamine receptor knockout mice indicate that these receptors are involved but not necessary for the subjective effects of cocaine. The selective D2 antagonist raclopride blocks the effects of cocaine in normal but not in D2 dopamine receptor KO mice. Studies with D5 KO mice indicate a lack of involvement of these receptors in the subjective effects of cocaine. Current studies with D4 dopamine receptor knockout mice indicate that this receptor contributes minimally, if at all, to the subjective effects of cocaine.
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