title: Abnormal GABAergic function and negative affect in schizophrenia.
abstract: Deficits in the γ-aminobutyric acid (GABA) system have been reported in postmortem studies of schizophrenia, and therapeutic interventions in schizophrenia often involve potentiation of GABA receptors (GABAR) to augment antipsychotic therapy and treat negative affect such as anxiety. To map GABAergic mechanisms associated with processing affect, we used a benzodiazepine challenge while subjects viewed salient visual stimuli. Fourteen stable, medicated schizophrenia/schizoaffective patients and 13 healthy comparison subjects underwent functional magnetic resonance imaging using the blood oxygenation level-dependent (BOLD) technique while they viewed salient emotional images. Subjects received intravenous lorazepam (LRZ; 0.01 mg/kg) or saline in a single-blinded, cross-over design (two sessions separated by 1-3 weeks). A predicted group by drug interaction was noted in the dorsal medial prefrontal cortex (dmPFC) as well as right superior frontal gyrus and left and right occipital regions, such that psychosis patients showed an increased BOLD signal to LRZ challenge, rather than the decreased signal exhibited by the comparison group. A main effect of reduced BOLD signal in bilateral occipital areas was noted across groups. Consistent with the role of the dmPFC in processing emotion, state negative affect positively correlated with the response to the LRZ challenge in the dmPFC for the patients and comparison subjects. The altered response to LRZ challenge is consistent with altered inhibition predicted by postmortem findings of altered GABAR in schizophrenia. These results also suggest that negative affect in schizophrenia/schizoaffective disorder is associated-directly or indirectly-with GABAergic function on a continuum with normal behavior.
authors.affiliation: Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Stephan F
authors.initials: SF
authors.lastname: Taylor
authors.affiliation: Department of Psychology, Duke University, Durham, NC, USA.
authors.forename: Elise
authors.initials: E
authors.lastname: Demeter
authors.affiliation: Department of Psychiatry, University of Illinois at Chicago and Mental Health Service, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA.
authors.forename: K Luan
authors.initials: KL
authors.lastname: Phan
authors.affiliation: Department of Psychology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Ivy F
authors.initials: IF
authors.lastname: Tso
authors.affiliation: Department of Radiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Welsh
mesh_terms: D000328:Adult; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D018592:Cross-Over Studies; D005260:Female; D018757:GABA Modulators / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008140:Lorazepam / Q000494:pharmacology / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D019964:Mood Disorders / Q000188:drug therapy / Q000209:etiology*; D010100:Oxygen / Q000097:blood; D010775:Photic Stimulation; D011618:Psychotic Disorders / Q000150:complications / Q000473:pathology; D012559:Schizophrenia / Q000150:complications* / Q000473:pathology*; D016037:Single-Blind Method; D014796:Visual Perception / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018757:GABA Modulators; D005680:gamma-Aminobutyric Acid; D008140:Lorazepam; D010100:Oxygen