Efficacy and side effects of baclofen and the novel GABA B receptor positive allosteric modulator CMPPE in animal models for alcohol and cocaine addiction

Abstract

Rationale: Preclinical studies suggest that the GABA B receptor is a potential target for treatment of substance use disorders. However, recent clinical trials report adverse effects in patients treated with the GABA B receptor agonist baclofen and even question efficacy. How can the discrepancy between preclinical and clinical findings be explained? Objective: To test efficacy and adverse effects of baclofen and the novel GABA B positive allosteric modulator (PAM) CMPPE in rat addiction models, which were developed in accordance with DSM. Methods: We used a well-characterized rat model of long-term alcohol consumption with repeated deprivation phases that result in compulsive alcohol drinking in a relapse situation, and a rat model of long-term intravenous cocaine self-administration resulting in key symptoms of addictive behavior. We tested repeated baclofen (0, 1, and 3 mg/kg; i.p.) and CMPPE doses (0, 10, and 30 mg/kg; i.p.) in relapse-like situations, in either alcohol or cocaine addicted-like rats. Results: Baclofen produced a weak anti-relapse effect at the highest dose in alcohol addicted-like rats, and this effect was mainly due to the treatment-induced sedation. CMPPE had a better profile, with a dose-dependent reduction of relapse-like alcohol drinking and without any signs of sedation. The cue-induced cocaine-seeking response was completely abolished by both compounds. Conclusion: Positive allosteric modulation of the GABA B receptor provides efficacy, and no observable side effects in relapse behavior whereas baclofen may cause, not only sedation, but also considerable impairment of food intake or metabolism. However, targeting GABA B receptors may be effective in reducing certain aspects of addictive-like behavior, such as cue-reactivity.