Restoring GABAB receptor expression in the ventral tegmental area of methamphetamine addicted mice inhibits locomotor sensitization and drug seeking behavior

Mohammad Hleihil; Dietmar Benke

doi:10.3389/fnmol.2024.1347228

Restoring GABA_B receptor expression in the ventral tegmental area of methamphetamine addicted mice inhibits locomotor sensitization and drug seeking behavior

Front Mol Neurosci. 2024 Feb 7:17:1347228. doi: 10.3389/fnmol.2024.1347228. eCollection 2024.

Authors

Mohammad Hleihil¹, Dietmar Benke^{1

2}

Affiliations

¹ Institute of Pharmacology and Toxicology, University of Zurich, Zürich, Switzerland.
² Neuroscience Center Zurich, University and ETH Zurich, Zürich, Switzerland.

Abstract

Repeated exposure to psychostimulants such as methamphetamine (METH) induces neuronal adaptations in the mesocorticolimbic dopamine system, including the ventral tegmental area (VTA). These changes lead to persistently enhanced neuronal activity causing increased dopamine release and addictive phenotypes. A factor contributing to increased dopaminergic activity in this system appears to be reduced GABA_B receptor-mediated neuronal inhibition in the VTA. Dephosphorylation of serine 783 (Ser783) of the GABA_B2 subunit by protein phosphatase 2A (PP2A) appears to trigger the downregulation GABA_B receptors in psychostimulant-addicted rodents. Therefore, preventing the interaction of GABA_B receptors with PP2A using an interfering peptide is a promising strategy to restore GABA_B receptor-mediated neuronal inhibition. We have previously developed an interfering peptide (PP2A-Pep) that inhibits the GABA_B receptors/PP2A interaction and thereby restores receptor expression under pathological conditions. Here, we tested the hypothesis that restoration of GABA_B receptor expression in the VTA of METH addicted mice reduce addictive phenotypes. We found that the expression of GABA_B receptors was significantly reduced in the VTA and nucleus accumbens but not in the hippocampus and somatosensory cortex of METH-addicted mice. Infusion of PP2A-Pep into the VTA of METH-addicted mice restored GABA_B receptor expression in the VTA and inhibited METH-induced locomotor sensitization as assessed in the open field test. Moreover, administration of PP2A-Pep into the VTA also reduced drug seeking behavior in the conditioned place preference test. These observations underscore the importance of VTA GABA_B receptors in controlling addictive phenotypes. Furthermore, this study illustrates the value of interfering peptides targeting diseases-related protein-protein interactions as an alternative approach for a potential development of selective therapeutic interventions.

Keywords: GABA receptor; addiction; interfering peptide; methamphetamine; protein phosphatase 2A; ventral tegmental area (VTA).

Grants and funding

The authors declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by the Swiss National Science Foundation, grant number 31003A_182325 to DB.