Objective Postmortem studies in schizophrenia reveal alterations in gene products that regulate the release and extracellular persistence of GABA. However, results of in vivo studies of schizophrenia measuring total tissue GABA with magnetic resonance spectroscopy (MRS) have been inconsistent. Neither the postmortem nor the MRS studies directly address the physiological properties of GABA neurotransmission. The present study addresses this question through an innovative positron emission tomography (PET) paradigm. Method The binding of [11C]flumazenil, a benzodiazepine-specific PET radiotracer, was measured before and after administration of tiagabine (0.2 mg/kg of body weight), a GABA membrane transporter (GAT1) blocker, in 17 off-medication patients with schizophrenia and 22 healthy comparison subjects. Increased extracellular GABA, through GAT1 blockade, enhances the affinity of GABAA receptors for benzodiazepine ligands, detected as an increase in [11C]flumazenil tissue distribution volume (VT). Results [11C]Flumazenil VT was significantly increased across all cortical brain regions in the healthy comparison group but not in the schizophrenia group. This lack of effect was most prominent in the antipsychotic-naive schizophrenia group. In this subgroup, [11C]flumazenil ΔVT in the medial temporal lobe was correlated with positive symptoms, and baseline [11C] flumazenil VT in the medial temporal lobe was negatively correlated with visual learning. In the healthy comparison group but not the schizophrenia group, [11C]flumazenil ΔVT was positively associated with gamma-band oscillation power. Conclusions This study demonstrates, for the first time, an in vivo impairment in GABA transmission in schizophrenia, most prominent in antipsychotic-naive individuals. The impairment in GABA transmission appears to be linked to clinical symptoms, disturbances in cortical oscillations, and cognition.

Objective Basic studies have demonstrated that optimal levels of prefrontal cortical dopamine are critical to various executive functions such working memory, attention, inhibitory control and risk/reward decisions--all of which are impaired in addictive disorders such as alcoholism. Based on this and imaging studies in alcoholics that have demonstrated less dopamine in the striatum, we hypothesized decreased dopamine transmission in the prefrontal cortex in alcoholism. To test this hypothesis, we used amphetamine and [11C]FLB 457 positron emission tomography (PET) to measure cortical dopamine transmission in a group of 21 recently abstinent alcoholics and matched healthy controls. Methods [11C]FLB 457 binding potential (BPND) was measured in subjects with kinetic analysis using the arterial input function both before and after 0.5 mg kg−1 of d-amphetamine. Results Amphetamine-induced displacement of [11C]FLB 457 binding potential (Δ BPND) was significantly smaller in the cortical regions in alcoholics compared to healthy controls. Cortical regions that demonstrated lower dopamine transmission in alcoholics included the dorsolateral prefrontal cortex, medial prefrontal cortex, orbital frontal cortex, temporal cortex and medial temporal lobe. Conclusions The results of this study for the first time unambiguously demonstrate decreased dopamine transmission in the cortex in alcoholism. Further research is necessary to understand the clinical relevance of decreased cortical dopamine as to whether it is related to impaired executive function, relapse, and outcome in alcoholism.

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The results of this study do not support alterations in the binding to NOP receptors in alcohol dependence. However, this finding does not necessarily rule out alterations in nociceptin transmission in alcohol dependence.

Post-traumatic stress disorder (PTSD) is a stress disorder that develops in only some individuals following a traumatic event. Data suggest that a substantial fraction of women recover after sexual violence. Thus, the investigation of stress and anti-stress neuropeptides in this sample has the potential to inform the neurochemistry of resilience following trauma. Nociceptin is an anti-stress neuropeptide in the brain that promotes resilience in animal models of PTSD. METHODS: [ 11 C]NOP-1A PET was used to measure the in vivo binding to nociceptin receptors in 18 college women who had experienced sexual violence irrespective of whether they met DSM-5 diagnostic criteria for PTSD. [ 11 C]NOP-1A data from 18 healthy controls was also included to provide a contrast with the sexual violence group. [ 11 C]NOP-1A total distribution volume (V T) in the regions of interest were measured with kinetic analysis using the arterial input function. The relationships between regional V T and Clinician-Administered PTSD Scale total symptom and subscale severity were examined using correlational analyses. RESULTS: No differences in [ 11 C]NOP-1A V T were noted between the sexual violence and control groups. V T in the midbrain and cerebellum were positively correlated with PTSD total symptom severity in the past month prior to PET. Intrusion/re-experiencing and avoidance subscale symptoms drove this relationship. Stratification of subjects by a DSM-5 PTSD diagnosis and contrasting their V T with that in controls showed no group differences. CONCLUSION: Decreased midbrain and cerebellum nociceptin receptors are associated with less severe PTSD symptoms. Medications that target nociceptin should be explored to prevent and treat PTSD.