title: Reducing prefrontal gamma-aminobutyric acid activity induces cognitive, behavioral, and dopaminergic abnormalities that resemble schizophrenia.
abstract: BACKGROUND
  Perturbations in gamma-aminobutyric acid (GABA)-related markers have been reported in the prefrontal cortex of schizophrenic patients. However, a preclinical assessment of how suppression of prefrontal cortex GABA activity may reflect behavioral and cognitive pathologies observed in schizophrenia is forthcoming.
  
  
  METHODS
  We assessed the effects of pharmacologic blockade of prefrontal cortex GABA(A) receptors in rats on executive functions and other behaviors related to schizophrenia, as well as neural activity of midbrain dopamine neurons.
  
  
  RESULTS
  Blockade of prefrontal cortex GABA(A) receptors with bicuculline (12.5-50 ng) did not affect working memory accuracy but did increase response latencies, resembling speed of processing deficits observed in schizophrenia. Prefrontal cortex GABA(A) blockade did not impede simple discrimination or reversal learning but did impair set-shifting in a manner dependent on when these treatments were given. Reducing GABA activity before the set-shift impaired the ability to acquire a novel strategy, whereas treatment before the initial discrimination increased perseveration during the shift. Latent inhibition was unaffected by bicuculline infusions before the preexposure/conditioning phases, suggesting that reduced prefrontal cortex GABA activity does not impair "learned irrelevance." GABA(A) blockade increased locomotor activity and showed synergic effects with a subthreshold dose of amphetamine. Furthermore, reducing medial prefrontal cortex GABA activity selectively increased phasic burst firing of ventral tegmental area dopamine neurons, without altering the their overall population activity.
  
  
  CONCLUSIONS
  These results suggest that prefrontal cortex GABA hypofunction may be a key contributing factor to deficits in speed of processing, cognitive flexibility, and enhanced phasic dopamine activity observed in schizophrenia.
authors.affiliation: Department of Psychology and Brain Research Centre, University of British Columbia, 2136 West Mall, Vancouver, BC, Canada.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Enomoto
authors.forename: Maric T
authors.initials: MT
authors.lastname: Tse
authors.forename: Stan B
authors.initials: SB
authors.lastname: Floresco
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001640:Bicuculline / Q000008:administration & dosage / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects*; D003463:Cues; D004193:Discrimination Learning / Q000187:drug effects; D004298:Dopamine / Q000502:physiology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D055724:Electrophysiological Phenomena; D018756:GABA Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D008845:Microinjections; D010775:Photic Stimulation; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000378:metabolism*; D012565:Schizophrenic Psychology; D055139:Sensory Gating / Q000187:drug effects; D013569:Synapses / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018765:Dopamine Uptake Inhibitors; D018756:GABA Antagonists; D005680:gamma-Aminobutyric Acid; D000661:Amphetamine; D004298:Dopamine; D001640:Bicuculline