title: Schizophrenia-like attentional deficits following blockade of prefrontal cortex GABAA receptors.
abstract: Attentional deficits are a core symptom of schizophrenia. Post-mortem analyses of the brains of schizophrenics reveal consistent abnormalities in γ-aminobutyric acid (GABA) interneurons indicative of reduced cortical GABA transmission, raising the possibility that this pathology contributes to attentional deficits. We examined whether blockade of prefrontal cortex (PFC) GABA(A) receptors with bicuculline (BMI) impairs attention in rats using the 5-choice serial reaction time task (5CSRTT). For comparison, we also examined whether administration of the GABA(A) receptor agonist muscimol (MUS) would improve attention. In parallel, we examined the effects of both manipulations on activity in an open field and on motivation using the intracranial self-stimulation (ICSS) test. BMI increased PFC neuronal activity, as reflected by increased Fos immunolabeling, and impaired attention, as reflected by decreased accuracy and increased omissions. Although increased omissions also may reflect reductions in locomotor activity or motivation, the overall pattern of effects does not support either of these interpretations: BMI did not affect locomotor activity, and it enhanced motivation in the ICSS test. MUS did not affect attention, although it increased impulsive behavior at a dose that suppressed PFC neuronal activity, as reflected by decreased Fos immunolabeling. These impulsivity effects are not due to altered locomotor activity (which was decreased) or motivation (which was not affected). Our data support the hypothesis that cortical GABA neurons have an important role in regulating attention and may have direct implications for the treatment of schizophrenia.
authors.affiliation: Department of Psychiatry, Behavioral Genetics Laboratory, Harvard Medical School, McLean Hospital, Belmont, MA, USA. tpaine@oberlin.edu
authors.forename: Tracie A
authors.initials: TA
authors.lastname: Paine
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Slipp
authors.forename: William A
authors.initials: WA
authors.lastname: Carlezon
mesh_terms: D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000139:chemically induced / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism* / Q000502:physiology; D012559:Schizophrenia / Q000139:chemically induced / Q000503:physiopathology*
chemical_list: D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A