title: Prefrontal gamma-aminobutyric acid type A receptor insertion controls cue-induced relapse to nicotine seeking.
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.
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics & Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam.
authors.forename: Bart R
authors.initials: BR
authors.lastname: Lubbers
authors.affiliation: Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Yvar
authors.initials: Y
authors.lastname: van Mourik
authors.affiliation: Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Dustin
authors.initials: D
authors.lastname: Schetters
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics & Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam.
authors.forename: August B
authors.initials: AB
authors.lastname: Smit
authors.affiliation: 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.
authors.forename: Taco J
authors.initials: TJ
authors.lastname: De Vries
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics & Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam. Electronic address: s.spijker@vu.nl.
authors.forename: Sabine
authors.initials: S
authors.lastname: Spijker
mesh_terms: D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D005108:Extinction, Psychological / Q000187:drug effects; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D009538:Nicotine / Q000008:administration & dosage; D010455:Peptides / Q000008:administration & dosage; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000378:metabolism; D012008:Recurrence; D012646:Self Administration; D013569:Synapses / Q000378:metabolism; D014029:Tobacco Use Disorder / Q000523:psychology*; D005680:gamma-Aminobutyric Acid
chemical_list: D058785:GABA-A Receptor Agonists; D010455:Peptides; D011963:Receptors, GABA-A; D017470:Receptors, Glutamate; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D009538:Nicotine
keywords: GABAA receptor; inhibitory plasticity; medial prefrontal cortex; nicotine addiction; reinstatement; self-administration