Effect of Gabapentin on GABA Concentration and Emotional Processing
Condition: Healthy
Study type: Observational

Summary: 
      This study will use magnetic resonance spectroscopy (MRS) and the drug gabapentin to examine
      the role of the brain chemical gamma-amino-butyric acid (GABA) in regulating emotions in
      healthy people. Gabapentin, which is used to treat epilepsy, increases GABA concentrations in
      the brain. MRS, similar to magnetic resonance imaging (MRI), is a diagnostic test that uses a
      magnetic field and radio waves to produce images of the brain.

      Non-smoking, healthy normal volunteers between 18 and 60 years of age may be eligible for
      this study. Candidates are screened with a medical history and physical examination,
      psychiatric evaluation, blood and urine tests, and an electrocardiogram (EKG).

      At three separate clinic visits, participants are given either gabapentin or a placebo (an
      inactive look-alike capsule). They take placebo at one visit, 600 mg of gabapentin at another
      visit, and 1200 mg of gabapentin at another visit. One hour after taking the capsules, the
      amount of GABA in the brain is measured by MRS. For this procedure, the subject lies on a
      table that moves into the MRI scanner (a narrow cylinder), wearing earplugs to muffle loud
      knocking and thumping sounds that occur during the scanning process. The procedure lasts
      about 45 to 60 minutes, during which the patient is asked to lie still for up to a few
      minutes at a time.
    

Detailed description: 
      Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the forebrain
      structures, and the GABAergic system has been found to have roles in attentional and learning
      processes, recognition of aversive stimuli, and regulation of emotion and behavior. Decreases
      in GABA have been associated with seizures, anxiety and mood disorders. Enhancement of GABA
      may result in anticonvulsive, anxiolytic, and mood-stabilizing effects.

      The GABA system has been proposed as a target for novel antidepressant and mood-stabilizing
      treatments. Recent studies suggest a GABAergic dysfunction in mood and anxiety disorders.
      Specifically, reduced GABA levels have been found in the occipital cortex of patients with
      major depression and panic disorder; and after therapy with selective serotonin reuptake
      inhibitors, an increase in occipital GABA concentrations has been observed in depressed
      patients and healthy volunteers.

      Gabapentin (GBP) is a relatively novel drug that has been approved for the treatment of
      epilepsy. The effects of GBP on brain amino acid neurotransmitters are not completely
      understood. GBP significantly increases brain GABA levels in humans after one hour of the
      first oral dose, although it does not seem to directly affect GABA-specific enzymes, GABA
      receptors, and GABA uptake. In vitro, GBP stimulates the enzyme glutamic acid decarboxylase
      that is involved in the synthesis of GABA.

      To date, studies that have examined the mechanism of action of GABA enhancing compounds using
      magnetic resonance spectroscopy (MRS) measured GABA exclusively in the occipital cortex due
      to technical limitations. Not surprisingly, associations between occipital GABA levels and
      cognitive measures and psychiatric symptom severity have not been found.

      Thanks to a novel MRS method developed by GE and implemented by NIH, reliable measurements of
      prefrontal GABA levels are now available. The current study is designed to estimate
      prefrontal GABA levels in a placebo-controlled double-blind study of GBP. It is aimed at
      evaluating the novel MRS method to estimate prefrontal GABA levels. Prefrontal GABA levels
      will be related to prefrontal functions including facial emotion recognition and response
      control. GABA MRS after GBP/placebo may be used as challenge paradigm for future studies
      aimed at elucidating GABAergic dysfunctions in mood and anxiety disorders. 10 healthy
      medication-free human subjects will be examined by GABA magnetic resonance spectroscopy in a
      controlled trial using placebo, 600mg, and 1200mg GBP.

      Given the potential role of GABA in the physiologic stress response, this protocol includes a
      pilot study that compares prefrontal GABA levels between shock/threat-of-shock and no-threat
      conditions in healthy volunteers. This part of the study may contribute to the elucidation of
      the role of the prefrontal GABAergic system in the processing of acute stress.
    

Keywords: Prefrontal GABA; Stress; Emotion Recognition; Differential Reward; Gabapentin; GABA; Prefrontal Cortex; Emotional Processing; Healthy Humans; Healthy Volunteer; HV