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

Preclinical studies suggest that the GABA receptor is a potential target for treatment of substance use disorders. However, recent clinical trials report adverse effects in patients treated with the GABA receptor agonist baclofen and even question efficacy. How can the discrepancy between preclinical and clinical findings be explained? To test efficacy and adverse effects of baclofen and the novel GABA positive allosteric modulator (PAM) CMPPE in rat addiction models, which were developed in accordance with DSM. 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. 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. Positive allosteric modulation of the GABA 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 receptors may be effective in reducing certain aspects of addictive-like behavior, such as cue-reactivity.