Effect of Gabapentin on GABA Concentration and Emotional Processing

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.