κ-opioid receptor activation modifies dopamine uptake in the nucleus accumbens and opposes the effects of cocaine

Coadministration of κ-opioid receptor agonists (κ-agonists) with cocaine prevents alterations in dialysate dopamine (DA) concentration in the nucleus accumbens (Acb) that occur during abstinence from repeated cocaine 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 κ-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 determined 3 d later. Repeated cocaine treatment increased E_d, whereas repeated U-69593 treatment decreased E_d, relative to controls. Coadministration of both drugs yielded intermediate E_d values not different from controls. In vitro DA uptake assays confirmed that repeated U-69593 treatment produces a doserelated, region-specific decrease in DA uptake and showed that acute U-69593 administration increases DA uptake in a norbinaltorphimine reversible manner. Repeated U-69593 also led to a decrease in [¹²⁵I]RTI-55 binding to the DA transporter (DAT), but did not decrease total DAT protein. These results demonstrate that κ-opioid receptor activation modulates DA uptake in the Acb in a manner opposite to that of cocaine: Repeated U-69593 administration decreases the basal rate of DA uptake, and acute U-69593 administration transiently increases DA uptake. κ-agonist treatment also alters DAT function. The action of κ-agonists on DA uptake or DAT binding, or both, may be the mechanism(s) mediating the previously reported "cocaine-antagonist" effect of κ-opioid receptor agonists.