Abnormal GABAergic Function and Negative Affect in Schizophrenia

Abstract

Deficits in the g-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.

Abnormal GABAergic function and face processing in schizophrenia: A pharmacologic-fMRI study

“…The full results of the VAS ratings are previously reported (Taylor et al, 2014). Critically, LRZ did not have an effect on drowsiness ratings.…”

“…In a recent study, we paired a benzodiazepine challenge and blood-oxygen-level dependent (BOLD) fMRI to map GABAergic mechanisms associated with affect processing in schizophrenia (Taylor et al, 2014). We used lorazepam (LRZ), a non-subtype selective benzodiazepine and an allosteric modulator of GABA receptors that potentiates GABA function (Olsen and Tobin, 1990), to probe GABAergic activity during passive viewing of emotionally salient images.…”

Searching for Cross-Diagnostic Convergence: Neural Mechanisms Governing Excitation and Inhibition Balance in Schizophrenia and Autism Spectrum Disorders

“…To this end, in ASD, long-term bumetanide administration, which decreases intracellular chloride and reinforces GABA’s inhibitory effect, enhanced BOLD activation during emotional face perception(139). Acute administration of benzodiazepines, which are GABA agonists, increased occipital and prefrontal BOLD signal while viewing emotional images in SCZ, though it decreased signal in the same regions in controls(140,141). These pharmacological studies are consistent with alterations in GABAergic and glutamatergic functioning across ASD and SCZ.…”

In vivo assessment of neurotransmitters and modulators with magnetic resonance spectroscopy: Application to schizophrenia

“…Altered GABAergic function is implicated in the pathophysiology of schizophrenia as evident through post-mortem studies (Hashimoto et al, 2008; Deng and Huang, 2006; Beneyto and Lewis, 2011) and challenge studies (Ahn et al, 2011; Taylor et al, 2013). Within the 1 H spectrum, GABA peaks arise at 1.89, 2.28, and 3.01 ppm, and GABA concentrations typically range from 1.3–1.9 mM (Govindaraju et al, 2000).…”