GBR12909 ANTAGONIZES THE ABILITY OF COCAINE TO ELEVATE EXTRACELLULAR LEVELS OF DOPAMINE

Rats were administered various IP doses of the high-affinity dopamine (DA) reuptake inhibitor 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[phenylpropyl]piperazine (GBR12909). The caudate nuclei were removed 60 min after drug administration and stored at -70-degrees-C. Striatal membranes were prepared later. The results demonstrated that GBR12909 produced a dose-dependent decrease in the binding of [H-3]cocaine or [H-3]GBR12935 to the DA transporter (ED50 about 10 mg/kg). Saturation binding studies with [H-3]GBR12935 showed that this was due to both an increase in the K(d), due to residual drug, and to a decrease in the B(max). At a dose of 25 mg/kg IP, GBR12909 produced a 50% decrease in the B(max), and a 3.4-fold increase in the K(d). In the in vivo microdialysis studies, GBR12909 (25 mg/kg IP) produced a modest, long-lasting and stable elevation of extracellular DA. Administration of cocaine through the microdialysis probe to rats pretreated with either saline or GBR12909 (25 mg/kg IP) produced a dose-dependent increase in extracellular DA in both groups. GBR12909 inhibited cocaine-induced increases in extracellular DA by about 50% at all doses. These data collectively indicate that at a dose sufficient to decrease by 50% the B(max) of [H-3]GBR12935 binding sites, GBR12909 antagonizes the ability of cocaine to elevate extracellular DA by 50%. Further studies will be needed to evaluate a possible role for GBR12909 in the medical treatment of cocaine addiction.