Reduced GABAA benzodiazepine receptor binding in veterans with post-traumatic stress disorder

Abstract

c-Aminobutyric acid (GABA A ) receptors are thought to play an important role in modulating the central nervous system in response to stress. Animal data have shown alterations in the GABA A receptor complex by uncontrollable stressors. SPECT imaging with benzodiazepine ligands showed lower distribution volumes of the benzodiazepine-GABA A receptor in the prefrontal cortex of patients with post-traumatic stress disorder (PTSD) in one, but not in another study. The objective of the present study was to assess differences in the benzodiazepine-GABA A receptor complex in veterans with and without PTSD using [ 11 C]flumazenil and positron emission tomography (PET). Nine drug naive male Dutch veterans with deployment related PTSD and seven male Dutch veterans without PTSD were recruited, and matched for age, region and year of deployment. Each subject received a [ 11 C]flumazenil PET scan and a structural magnetic resonance imaging scan. Dynamic 3D PET scans with a total duration of 60 min were acquired, and binding in template based and manually defined regions of interest (ROI) was quantified using validated plasma input and reference tissue models. In addition, parametric binding potential images were compared on a voxel-by-voxel basis using statistical parametric mapping (SPM2). ROI analyses using both template based and manual ROIs showed significantly reduced [ 11 C]flumazenil binding in PTSD subjects throughout the cortex, hippocampus and thalamus. SPM analysis confirmed these results. The observed global reduction of [ 11 C]flumazenil binding in patients with PTSD provides circumstantial evidence for the role of the benzodiazepine-GABA A receptor in the pathophysiology of PTSD and is consistent with previous animal research and clinical psychopharmacological studies.

Targeting the Modulation of Neural Circuitry for the Treatment of Anxiety Disorders

“…Dynamic three-dimensional PET scans show that the BZD-GABA A R may play a role in the pathophysiology of PTSD, a finding that is consistent with previous animal and clinical pharmacological studies (Geuze et al, 2008). In this study, radiolabeled [ 11 C]flumazenil was Fig.…”

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

“…Nearly all neuropsychiatric disorders include dysfunctional GABA system components: schizophrenia (Hashimoto et al, 2008a), bipolar disorder Guidotti et al, 2000a), anxiety (Mohler, 2012), depression (Gao et al, 2013;Thompson Ray et al, 2011), panic disorder (Malizia et al, 1998), posttraumatic stress disorder (Geuze et al, 2008), attention deficit hyperactivity disorder (Edden et al, 2012), autism (Fatemi et al, 2010(Fatemi et al, , 2002, Rett syndrome (Blue et al, 1999;Chao et al, 2010), epilepsy (Kang and Macdonald, 2009), and others (Marin, 2012). There is also some overlap in environmental risk factors such as immune system activation during development in schizophrenia and autism (Michel et al, 2012;Patterson, 2009).…”

Decreased corticolimbic allopregnanolone expression during social isolation enhances contextual fear: A model relevant for posttraumatic stress disorder

“…This procedure also reproduces several aspects of exaggerated emotional reactivity, including enhanced fear conditioning and impaired fear extinction, which develop in PTSD patients when they are reexposed to events that symbolize an aspect of the triggering traumatic event (15,32,33). A variety of alterations in GABAergic neurotransmission have been identified in patients with PTSD, including: (i) the reduced sedative and anxyolitic action of classical benzodiazepines (34)(35)(36), (ii) the decreased frontocortical benzodiazepine recognition site binding detected in Balkan and Vietnam War veterans (37,38), and (iii) a decrease of Allo levels in the CSF of premenopausal women that negatively correlates with PTSD symptoms, negative moods, and comorbid depressive symptoms (20). Of note, Allo levels were found to be decreased in the whole PTSD group, but were lowest in those patients with PTSD and comorbid depression (20).…”