GABAA Negative Modulation Selectively Attenuates Cocaine Self‐Administration In Rats

Abstract

GABAA receptors are critical to normal CNS functioning, abundant in brain areas involved in motivational processes and have been implicated in neurological disorders including substance use disorders. Modulation of GABAA receptors can alter the effects of abused drugs including those which do not directly interact with GABAA receptors. Our previous data showed that a low efficacy benzodiazepine‐site negative GABAA modulator will attenuate both toluene and methamphetamine‐facilitated intracranial self‐stimulation in mice and attenuate methamphetamine‐stimulated extracellular dopamine levels in the nucleus accumbens of mice in vivo. Given the critical placement of GABAA receptor populations within dopaminergic drug reward pathways, the current study investigated the hypothesis that negative allosteric modulation of GABAA receptors selectively alters reward circuitry to reduce the abuse‐related effects of cocaine. The effects of the negative GABAA modulator Ro 15,4513 on cocaine self‐administration was examined in adult male Sprague‐Dawley rats. Two groups of rats were trained on a fixed‐ratio 5 (FR5) schedule to self‐administer intravenous injections of 0.1 or 0.3 mg/kg/infusion cocaine in daily 2‐hr sessions. To further assess the selectivity of GABAA negative modulation for altering cocaine's effects, a third group of rats was trained to respond under a FR5 schedule for 45‐mg food pellets. After reaching stable levels of performance the rats were pretreated with vehicle, 0.3, 1 or 3 mg/kg intraperitoneal Ro15‐4513 prior to the 2‐hr operant test sessions. Each test session was separated by at least 3 days of training to allow Ro 15‐4313 washout and reestablish stable baseline rates of lever pressing behavior. Ro15‐4513 dose‐dependently attenuated cocaine self‐administration at both the 0.1 and 0.3 mg/kg/infusion cocaine self‐administration doses with responding almost completely eliminated by 3 mg/kg Ro 15‐4513. In contrast, the same doses of Ro15‐4513 had minimal effects on rates of food reinforced lever‐pressing. These data demonstrate that negative GABAA receptor modulation will attenuate intravenous cocaine self‐administration in male rats at doses that do not impact food‐maintained performance. Overall, our studies and prior data suggest negative modulation of the benzodiazepine‐site on GABAA receptors may be a promising pathway for the development of novel broad spectrum pharmacotherapeutics for substance abuse treatment.