Bart R Lubbers1, Yvar van Mourik2, Dustin Schetters2, August B Smit1, Taco J De Vries3, Sabine Spijker4. 1. Department of Molecular and Cellular Neurobiology, Center for Neurogenomics & Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam. 2. Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. 3. Department of Molecular and Cellular Neurobiology, Center for Neurogenomics & Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam; Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. 4. Department of Molecular and Cellular Neurobiology, Center for Neurogenomics & Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam. Electronic address: s.spijker@vu.nl.
Abstract
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 (GABAA) receptor subunit γ2 (TAT-GABAγ2) and muscimol, a GABAA 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, 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 relapse. Increasing GABAA 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. GABAA receptor-mediated neurotransmission in the dorsal mPFC constitutes a possible future therapeutic target for maintaining smoking abstinence.
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 (GABAA) receptor subunit γ2 (TAT-GABAγ2) and muscimol, a GABAA 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, 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 relapse. Increasing GABAA 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. GABAA receptor-mediated neurotransmission in the dorsal mPFC constitutes a possible future therapeutic target for maintaining smoking abstinence.
Authors: Roeland F Struik; Nathan J Marchant; Roel de Haan; Huub Terra; Yvar van Mourik; Dustin Schetters; Madison R Carr; Marcel van der Roest; Tim S Heistek; Taco J De Vries Journal: Neuropsychopharmacology Date: 2019-06-26 Impact factor: 7.853
Authors: Bart R Lubbers; Mariana R Matos; Annemarie Horn; Esther Visser; Rolinka C Van der Loo; Yvonne Gouwenberg; Gideon F Meerhoff; Renato Frischknecht; Constanze I Seidenbecher; August B Smit; Sabine Spijker; Michel C van den Oever Journal: Neuropsychopharmacology Date: 2015-12-29 Impact factor: 7.853
Authors: Jayme R McReynolds; Elizabeth M Doncheck; Yan Li; Oliver Vranjkovic; Evan N Graf; Daisuke Ogasawara; Benjamin F Cravatt; David A Baker; Qing-Song Liu; Cecilia J Hillard; John R Mantsch Journal: Biol Psychiatry Date: 2017-10-06 Impact factor: 13.382