Differential interaction of GBR 12909, a dopamine uptake inhibitor, with cocaine and methamphetamine in rats discriminating cocaine.

Abstract

Inhibitors of neuronal dopamine uptake, such as GBR 12909, decrease IV cocaine self-administration by laboratory animals and have been proposed as potential therapeutic agents for abuse of psychomotor stimulant drugs. This study was performed to determine how GBR 12909 alters the discriminative stimulus effects of methamphetamine and cocaine. Rats were trained to discriminate between IP injections of 10 mg/kg cocaine and saline and were tested for stimulus generalization to cocaine, GBR 12909, and methamphetamine. Based upon the ED50 of the individual drugs, combinations of GBR 12909 and either cocaine or methamphetamine were tested that comprised a) 1 part GBR 12909 and 2 parts cocaine or methamphetamine, or b) 2 parts GBR 12909 and 1 part cocaine or methamphetamine. GBR 12909 and cocaine were equipotent and 30-fold less potent than methamphetamine in producing cocaine-like discriminative effects. GBR 12909 and cocaine produced cocaine-like discriminative effects synergistically in the ratio of 1 part GBR 12909:2 parts cocaine (0.16+0.32 to 1.92+ 3.87 mg/kg) and nearly synergistically in the ratio of 2 parts GBR 12909:1 part cocaine (0.32+0.16 to 3.92+ 1.91 mg/kg). GBR 12909 and methamphetamine (0.32+0.02 to 3.20+0.22 mg/kg or 0.65+0.01 to 6.53+0.1 mg/kg) were simply additive in both sets of fixed-ratio dose combinations. The synergy of GBR 12909 and cocaine and the additivity of GBR 12909 and methamphetamine run counter to the presumed mechanisms of action of these drugs at dopamine nerve terminals, which might have implications for the use of GBR 12909 in the treatment of addiction to cocaine or amphetamines.