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The Journal of Neuroscience, 0000, 20:RC98:1-4

RAPID COMMUNICATION
Dopamine D₅ Receptors in Nucleus Accumbens Contribute to the Detection of Cocaine in Rats

Malgorzata Filip¹, Mary L. Thomas², and Kathryn A. Cunningham²

¹ Institute of Pharmacology, Polish Academy of Sciences, 31-343 Krakow, Poland, and ² Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555-1031

Dopamine D₁/D₅ receptor antagonism has been shown to block the euphoric and stimulatory effects of cocaine in humans and rats. In the present study, rats trained to discriminate the presence of cocaine (10 mg/kg) from its absence were used to analyze the functional contribution of D₁ (D₁R) versus D₅ (D₅R) receptors in the nucleus accumbens, an important neural site for the actions of cocaine. Bilateral microinfusion into the nucleus accumbens of an antisense oligonucleotide directed at the D₅R (0.75 nmol/0.3 µl per side, two times per day for 3 d) elicited a downward shift in the dose-effect curve for cocaine with a suppression of peak efficacy; the dose of cocaine estimated to elicit 50% drug-lever responding (ED₅₀) was 6.71 mg/kg when assessed 12 hr after the D₅R antisense oligonucleotide compared to the control ED₅₀ of 1.83 mg/kg and to the ED₅₀ of 1.75 mg/kg established 7 d after the last D₅R antisense oligonucleotide infusion. The D₁R antisense and scrambled oligonucleotide (0.75 nmol/0.3 µl per side, two times per day for 3 d) were both ineffective. Thus, using drug discrimination techniques that model the subjective effects of cocaine, we show that responsiveness to cocaine is dramatically attenuated after interference with the process of translation of the D₅R mRNA to its protein product. These findings suggest that D₅R is a functionally important target site for the indirect actions of cocaine and that rigorous investigations of the function of D₅R may help guide the discovery of strategies for pharmacotherapy in cocaine dependence.

Key words: behavior; cocaine; D₁ receptor; D₅ receptor; D1a receptor; D1b receptor; discriminative stimulus effects; dopamine

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