Rimcazole Attenuates the Cocaine‐Induced Stimulation of Mesolimbic Dopamine related to its Abuse and Dependence

Abstract

Rimcazole (RIM) is a sigma receptor (σR) antagonist that also has affinity for the dopamine (DA) transporter (DAT). Despite this DAT affinity, RIM lacks stimulant effects and dose‐dependently attenuates ambulatory effects of cocaine (COC). RIM and its analogs decrease COC self‐administration in rats (JPET 339: 662), an effect that is obtained neither with selective σR antagonists nor standard DAT blockers.Thus, we tested RIM (1–17 mg/kg i.p.) alone and in combination with increasing doses of COC that maintain self‐administration (0.1–1.0 mg/kg i.v.), on stimulation of mesolimbic DA in Sprague Dawley rats implanted with a microdialysis probes in the accumbens shell.RIM dose‐dependently attenuated COC‐induced stimulation of DA levels at doses that had no effects on DA levels when administered alone. Previous studies suggest that the attenuation of COC self‐administration produced by RIM is due to the combined actions at σRs and the DAT as combinations of selective DAT inhibitors and selective σR produced effects like those or RIM.Thus, the present study indicates that not only can combined DAT and σR inhibition decrease cocaine self administration, it also can decrease its neurochemical substrates suggesting that combined actions at these two targets may serve as a new strategy for discovery of novel compounds for development as medications for stimulant abuse.