Dopamine D5 receptors in nucleus accumbens contribute to the detection of cocaine in rats.

Dopamine D(1)/D(5) 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 D(1) (D(1)R) versus D(5) (D(5)R) 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 D(5)R (0. 75 nmol/0.3 microl 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 (ED(50)) was 6.71 mg/kg when assessed 12 hr after the D(5)R antisense oligonucleotide compared to the control ED(50) of 1.83 mg/kg and to the ED(50) of 1.75 mg/kg established 7 d after the last D(5)R antisense oligonucleotide infusion. The D(1)R antisense and scrambled oligonucleotide (0.75 nmol/0.3 microl 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 D(5)R mRNA to its protein product. These findings suggest that D(5)R is a functionally important target site for the indirect actions of cocaine and that rigorous investigations of the function of D(5)R may help guide the discovery of strategies for pharmacotherapy in cocaine dependence.