Pharmacology Of Dopamine Receptor Systems

National Institute On Drug Abuse

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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. Both DA D2R KO and HET mice showed reduced levels of locomotor activity compared to WT mice. Cocaine dose-dependently stimulated activity in each genotype, with the highest level of activity induced in the DA D2R WT mice. All three genotypes acquired the discrimination of 10 mg/kg cocaine; tested doses of 1.0 - 10.0 mg/kg produced dose-related increases in the number of cocaine-appropriate responses. The D2/D3 DAR antagonist, raclopride, dose-dependently shifted the cocaine dose-effect curve to the right in DA D2R WT and HET mice. However, in DA D2R KO mice raclopride was inactive as an antagonist. These data indicate an involvement of D2 dopamine receptors in the locomotor-stimulating effects and the subjective discriminative-stimulus effects of cocaine in WT subjects. However, the D2 receptor is not necessary for the effects, suggesting redundant dopaminergic mechanisms for the discriminative-stimulus interoceptive effects of cocaine. The role of D4 and D5 DA receptors in the behavioral effects of cocaine was also examined in KO mice. The D4 KO mice were more sensitive to the locomotor stimulant and subjective effects of cocaine compared to WT littermates. The dose-effect curve for cocaine was significantly shifted to the left approximately 2.5-fold in the DA D4R KO mice (ED50 value = 0.50 mg/kg) compared to their WT littermates (ED50 value = 2.6 mg/kg). Cocaine was also a more potent stimulator of locomotor activity in the DA D4R KO mice compared to WT littermate mice. The present results on the stimulation of activity and interoceptive/subjective effects of cocaine are consistent with the previously reported disregulation of dopamine synthesis in DA D4R KO mice, and further suggest a role of the DA D4R in vulnerability to stimulant abuse. Recent data suggest that dopamine (DA) D1-like receptor full agonists may be potential pharmacotherapeutic agents for treating cocaine abuse. The structurally novel isochroman D1-like agonist, A-77636, was investigated for this potential use. The interactions of cocaine and A-77636 were compared to those obtained with the better investigated benzazepine D1-like dopamine agonists, SKF 82958 and SKF 81297. Each of the D1-like agonists produced a dose-related decrease in cocaine-induced locomotor activity. Each of the drugs only partially substituted for cocaine. Both SKF 81297 and SKF 82958 shifted the cocaine dose-effect curve approximately three fold to the left. In contrast to the other two D1-like agonists, A-77636 either did not affect the cocaine dose-effect curve or shifted it to the right. These results suggest fundamental differences in the actions of these D1 agonists. Because A-77636 consistently attenuated the present effects of cocaine, it may prove more useful than the others as a pharmacotherapy to treat cocaine abuse. The D1-like receptor partial agonist SKF 38393 has been used as a prototype D1 agonist. Studies of effects of D1 agonists on adenylyl cyclase have identified SKF 38393 as a partial agonist. In studies of rats trained to discriminate the drug from saline a number of other D1-like agonists fully substituted for SKF 38393. However, the full D1-like agonist SKF 82958 did not fully substitute. This result suggests that second messenger effects other than stimulation of cyclic AMP formation may play an important role in the discriminative-stimulus effects of the D1-like agonist, SKF 38393. Early psychopharmacologists often explained the behavioral effects of drugs as due to changes in the hypothetical construct of motivation, implying that drug effects would depend on the inherent properties of the reinforcer that maintains responding. Alternative explanations have related the behavioral effects of drugs to the scheduling of reinforcers, and the patterns and rates of responding maintained. We reviewed the literature on the influence on drug effects of the type of reinforcer that maintains responding. Studies that examined the effects of drugs on behaviors maintained by different reinforcers were compared with studies that examined behaviors maintained by the same reinforcer under various conditions. Over a wide range of conditions, the effects of drugs depend more on the schedule-controlled patterns and rates of responding than on the particular reinforcer. However, there are some conditions under which the reinforcer that maintains behavior can also determine drug effects. Under some conditions drug effects are ostensibly consistent with explanations in terms of traditional hypothetical constructs, though under a wide range of other conditions they are not. A more general understanding of the behavioral effects of drugs comes from directing the emphasis of research away from hypothetical constructs and towards the empirically defined determinants of the behavioral effects of drugs.