kappa-Opioid receptor activation modifies dopamine uptake in the nucleus accumbens and opposes the effects of cocaine

Coadministration of kappa -opioid receptor agonists (kappa -agonists) with cocaine prevents alterations in dialysate dopamine (DA) concentration in th e nucleus accumbens (Acb) that occur during abstinence from repeated cocain e treatment. Quantitative microdialysis was used to determine the mechanism producing these effects. Rats were injected with cocaine (20 mg/kg, i.p.), or saline, and the selective kappa -agonist U-69593 (0.32 mg/kg, s.c.), or vehicle, once daily for 5 d. Extracellular DA concentration (DA(ext)) and extraction fraction (E-d), an indirect measure of DA uptake, were determine d 3 d later. Repeated cocaine treatment increased E-d, whereas repeated U-6 9593 treatment decreased E-d, relative to controls. Coadministration of bot h drugs yielded intermediate Ed values not different from controls. In vitr o DA uptake assays confirmed that repeated U-69593 treatment produces a dos e-related, region-specific decrease in DA uptake and showed that acute U-69 593 administration increases DA uptake in a norbinaltorphimine reversible m anner. Repeated U-69593 also led to a decrease in [I-125] RTI-55 binding to the DA transporter (DAT), but did not decrease total DAT protein. These re sults demonstrate that kappa -opioid receptor activation modulates DA uptak e in the Acb in a manner opposite to that of cocaine: repeated U-69593 admi nistration decreases the basal rate of DA uptake, and acute U-69593 adminis tration transiently increases DA uptake. kappa -agonist treatment also alte rs DAT function. The action of kappa -agonists on DA uptake or DAT binding, or both, may be the mechanism(s) mediating the previously reported "cocain e-antagonist" effect of kappa -opioid receptor agonists.