Prefrontal Gamma-Aminobutyric Acid Type A Receptor Insertion Controls Cue-Induced Relapse to Nicotine Seeking

Background 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 relapse to nicotine seeking. Methods Using an intravenous self-administration model, we studied glutamate and gamma-aminobutyric acid receptor regulation in the synaptic membrane fraction of the rat mPFC following extinction and cue-induced relapse to nicotine seeking. Subsequently, we locally intervened at the level of GABAergic signaling by using a mimetic peptide of the GABA receptor associated protein–interacting domain of GABA type A (GABA A ) receptor subunit γ2 (TAT-GABAγ2) and muscimol, a GABA A receptor agonist. Results Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and N -methyl-D-aspartate receptors were not regulated after the 30-min relapse test. However, GABA A receptor subunits α1 and γ2 were upregulated, and interference with GABA A receptor insertion in the cell membrane using the TAT-GABAγ2 peptide in the dorsal mPFC, but not the ventral mPFC, significantly increased responding during relapse. Increasing GABA A transmission with muscimol in the dorsal and ventral mPFC attenuated relapse. Conclusions These data indicate that cue-induced relapse entails a GABAergic plasticity mechanism that limits nicotine seeking by restoring inhibitory control in the dorsal mPFC. GABA A receptor–mediated neurotransmission in the dorsal mPFC constitutes a possible future therapeutic target for maintaining smoking abstinence.