title: Ventral tegmental area GABA neurons and opiate motivation.
abstract: BACKGROUND
  Past research has demonstrated that when an animal changes from a previously drug-naive to an opiate-dependent and withdrawn state, morphine's motivational effects are switched from a tegmental pedunculopontine nucleus (TPP)-dependent to a dopamine-dependent pathway. Interestingly, a corresponding change is observed in ventral tegmental area (VTA) GABAA receptors, which change from mediating hyperpolarization of VTA GABA neurons to mediating depolarization.
  
  
  OBJECTIVE
  The present study investigated whether pharmacological manipulation of VTA GABAA receptor activity could directly influence the mechanisms underlying opiate motivation.
  
  
  RESULTS
  Using an unbiased place conditioning procedure, we demonstrated that in Wistar rats, intra-VTA administration of furosemide, a Cl(-) cotransporter inhibitor, was able to promote a switch in the mechanisms underlying morphine's motivational properties, one which is normally observed only after chronic opiate exposure. This behavioral switch was prevented by intra-VTA administration of acetazolamide, an inhibitor of the bicarbonate ion-producing carbonic anhydrase enzyme. Electrophysiological recordings of mouse VTA showed that furosemide reduced the sensitivity of VTA GABA neurons to inhibition by the GABAA receptor agonist muscimol, instead increasing the firing rate of a significant subset of these GABA neurons.
  
  
  CONCLUSIONS
  Our results suggest that the carbonic anhydrase enzyme may constitute part of a common VTA GABA neuron-based biological pathway responsible for controlling the mechanisms underlying opiate motivation, supporting the hypothesis that VTA GABAA receptor hyperpolarization or depolarization is responsible for selecting TPP- or dopamine-dependent motivational outputs, respectively.
authors: Institute of Medical Science, Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, M5S 3E1, Canada. r_kee@yahoo.com
authors: Ryan
authors: R
authors: Ting-A-Kee
authors: Hector
authors: H
authors: Vargas-Perez
authors: Jennifer K
authors: JK
authors: Mabey
authors: Samuel I
authors: SI
authors: Shin
authors: Scott C
authors: SC
authors: Steffensen
authors: Derek
authors: D
authors: van der Kooy
mesh_terms: D000086:Acetazolamide / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D004594:Electrophysiology; D005665:Furosemide / Q000494:pharmacology; D055879:Gene Knock-In Techniques; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009042:Motivation / Q000187:drug effects*; D009118:Muscimol / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D011963:Receptors, GABA-A; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D009020:Morphine; D005665:Furosemide; D000086:Acetazolamide
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