Pharmacology Of Dopamine Receptor Systems

National Institute On Drug Abuse

Investigators

Linked publications & trials

Abstract

The roles of specific dopamine (DA) receptors in the behavioral effects of cocaine, including its locomotor stimulant and interoceptive discriminative-stimulus, 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. Studies from other laboratories have suggested that DA D2R KO mice self administer more cocaine than WT mice. Our studies suggest that this difference is due to a decrease in the sensitivity of behavior to non-specific effects of cocaine in KO compared to WT mice, rather than a difference in the reinforcing effects of cocaine in the two genotypes. Further studies in our laboratory are examining general differences in reinforcement processes among the genotypes rather than a change in the specific reinforcing effects of cocaine. DA D4R KO mice were more sensitive to the locomotor stimulant and subjective effects of cocaine compared to WT littermates; the ED50 value in DA D4R KO mice was 0.50 mg/kg compared to 2.6 mg/kg in their WT littermates. Raclopride, which has low affinity for the DA D4R shifted the cocaine dose-effect curve in both DA D4R KO and WT mice. The present findings is consistent with an inhibitory role of the DA D4R in the expression of DA D2R activity. The removal of this inhibitory effect in the DA D4R KO mice, would underlie the enhanced sensitivity to stimulant drugs in DA D4R KO compared to WT mice. Dopamine D1-like antagonists block several effects of cocaine, including its locomotor-stimulant and discriminative-stimulus effects. Because these compounds generally lack selectivity among the dopamine D1 and D5 receptors, the specific roles of the subtypes have not been determined. Dopamine D5 receptor knockout (DA D5R KO), heterozygous (HET) and wild-type (WT) mice were used to study the role of D5 dopamine receptors in the effects of cocaine. Cocaine dose-dependently stimulated locomotor activity in each genotype, with both DA D5R KO and HET mice showing reduced levels of locomotor activity compared to WT mice. All three genotypes acquired the discrimination of 10 mg/kg cocaine. The dopamine antagonist, SCH 39166, produced a dose-dependent rightward shifts in the cocaine dose-effect curve in all genotypes, with similar apparent affinities. These data suggest an involvement of DA D5R in the locomotor stimulant effects of cocaine. However, there appears to be little involvement of the DA D5R in the discriminative-stimulus effects of cocaine, as each genotype acquired the discrimination with equal sensitivity. In addition, the antagonism data suggest a role of the D1 receptor in the behavioral effects of cocaine. 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 behavioral assays and their effectiveness biochemically has not been forthcoming. The present study compared the discriminative-stimulus effects of the D1-like partial agonist SKF 38393 with several other D1-like agonists, an indirect agonist, cocaine, and a D2-like agonist, quinpirole. Rats were trained to discriminate SKF 38393 (5.6 mg/kg) from vehicle. Under this schedule, 30 consecutive responses on one of two keys were reinforced with food presentation after a pre-session injection of 5.6 mg/kg SKF 38393, and 30 consecutive responses on the alternate key were reinforced after saline injection. When daily performances were stable, substitution patterns for several compounds were assessed during test sessions in which 30 consecutive responses on either key were reinforced. The D1-like agonist, SKF 75670, fully substituted for SKF 38393, whereas the agonists, SKF 77434, SKF 82958 and CY 208,243, only partially substituted (maximum drug-appropriate responding 49-68%). Quinpirole and cocaine, each produced only saline-appropriate responding. Though only a small number of compounds were examined, there was a direct relation between ED50 values for substitution and in vivo binding affinities for D1-like receptors. SKF 82958, which is considered a full agonist based on cyclic AMP accumulation was less effective in substituting for SKF 38393 (66%) than was the partial agonist SKF 75670 (100 %). There was a greater correspondence between discriminative-stimulus effectiveness and inositol phosphate accumulation than there was for adenylyl cyclase. The present results suggest that second messenger effects other than stimulation of cyclic AMP formation may play an important role in the behavioral effects of DA D1-like agonists.