Prefrontal GABAA receptor insertion controls cue-induced relapse to nicotine seeking

Current smoking cessation therapies offer limited success, as relapse rates remain high. Nicotine, which is the major component of tobacco smoke, is thought to be primarily responsible for the addictive properties of tobacco. However, little is known about the molecular mechanisms underlying nicotine relapse, hampering development of more effective therapies. The objective of this study was to elucidate the role of medial prefrontal cortex (mPFC) glutamatergic and gamma-aminobutyric acid (GABA)ergic receptors in controlling reinstatement of nicotine seeking. Using an intravenous self-administration model, we studied glutamate and GABA receptor regulation in the synaptic membrane fraction of the rat mPFC following extinction and cue-induced reinstatement of nicotine seeking. Subsequently, we locally intervened at the level of GABAergic signaling by using a mimetic peptide of the GABA receptor associa ted protein (GABARAP)-interacting domain of GABA type A (GABAA) receptor subunit γ2 (TATGABAγ2) and muscimol, a GABAA receptor agonist. Alpha-amino-3-hydroxy-5-methyl-4isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors were not regulated after the 30-minute reinstatement test. However, GABAA receptor subunits α1 and γ2 were upregulated, and interference with GABAA receptor insertion in the cell membrane using the TAT-GABAγ2 peptide in the dorsal mPFC, but not the ventral mPFC, significantly increased responding during reinstatement. Increasing GABAA transmission with muscimol in the dorsal and ventral mPFC attenuated reinstatement. These data indicate that cue-induced reinstatement entails a GABAergic plasticity mechanism that limits nicotine see king by restoring inhibitory control in the dorsal mPFC. GABAA receptor-mediated neurotransmission in the dorsal mPFC constitutes a possible future therapeutic target for maintaining smoking abstinence.