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

Abstract

Rationale

Preclinical studies suggest that the GABAB receptor is a potential target for treatment of substance use disorders. However, recent clinical trials report adverse effects in patients treated with the GABAB 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 GABAB 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 GABAB 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 GABAB receptors may be effective in reducing certain aspects of addictive-like behavior, such as cue-reactivity.

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Acknowledgements

We would like to thank Sabrina Koch and Elena Büchler for the excellent technical assistance.

Funding

Financial support for this work was provided by the Bundesministerium für Bildung und Forschung (e:Med program, FKZ: 01ZX1311A (Spanagel et al. 2013)). TTT was funded by CAPES Foundation, Ministry of Education of Brazil, Brasília – DF 70040-020, Brazil.

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Correspondence to Valentina Vengeliene.

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Vengeliene, V., Takahashi, T.T., Dravolina, O.A. et al. Efficacy and side effects of baclofen and the novel GABAB receptor positive allosteric modulator CMPPE in animal models for alcohol and cocaine addiction. Psychopharmacology 235, 1955–1965 (2018). https://doi.org/10.1007/s00213-018-4893-9

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  • DOI: https://doi.org/10.1007/s00213-018-4893-9

Keywords

  • Addiction
  • Ethanol
  • Cocaine
  • Relapse
  • Baclofen
  • CMPPE