Effect of GABAA Partial Inverse Agonists on Drug‐facilitated ICSS Reward

Abstract

We examined the ability of gamma-aminobutyric acid A receptor (GABAA) partial inverse agonists Ro15-4513 and FG-7142 and the antagonist flumazenil to block the reward-facilitating effects of methamphetamine on intracranial self-stimulation (ICSS) using a rate-frequency procedure. A total of 13 adult male C57BL6/J mice implanted with chronic bipolar stimulating electrodes directed toward the medial forebrain bundle and served as subjects. Following surgery, mice were trained to respond on an operant lever for electrical stimulation in 10 one min trials descending each subsequent min. A dose of 3 mg/kg methamphetamine robustly facilitated operant responding for ICSS (Top Figure). When administered alone, doses of 1 and 3 mg/kg flumazenil; 0.3 and 1 mg/kg RO15-4513; 0.1, 0.3 and 1 mg/kg FG-7142 did not significantly affect ICSS compared to the vehicle control. Higher doses of RO15-4513 and FG-7142 significantly decreased responding for ICSS relative to the vehicle control. Preadministration of flumazenil had no effect on methamphetamine facilitated ICSS. However, doses of 0.3 and 1 mg/kg RO15-4513, which themselves did not significantly attenuate ICSS, decreased the ICSS facilitation produced by 3 mg/kg methamphetamine (Bottom Figure). Similarly, 0.3 and 1 mg/kg FG-7142 dose-dependently decreased methamphetamine-facilitated ICSS. These results suggest an important role of GABAA receptors in modulating methamphetamine's reward-facilitating effects as well as the possibility that negative GABAA receptor modulation may have therapeutic value for the treatment of substance abuse disorders.