Effect of Gabapentin Administration on GABA and BOLD Signal in Visual Cortex of Healthy Men and Women
Ravi Prakash Reddy Nanga1,2, Kosha Ruparel2, Dina Appleby2, Mark Elliott1, Hari Hariharan1, Ravinder Reddy1, and Neill C Epperson2,3,4,5

1Radiology, University of Pennsylvania, Philadelphia, PA, United States, 2Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States, 3Obstetrics and Gynecology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States, 4Penn Center for the Study of Sex and Gender in Health, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States, 5Penn Center for Women’s Behavioral Wellness, Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States

Synopsis

We explored the potential for sex differences in brain Gamma-aminobutyric acid (GABA), glutamate (Glut) and neural response to an acute dose of gabapentin by using proton magnetic resonance spectroscopy (1H-MRS) followed by functional magnetic resonance imaging (fMRI) at 7T.

Background

GABA and Glut, which are primary inhibitory and excitatory neurotransmitters, respectively, in humans, have been implicated in numerous neurological, psychiatric and substance abuse conditions for which sex differences abound1,2. Here, we have tested whether sex differences play a role in regional brain GABA and Glut levels and blood oxygen level dependent (BOLD) signal in response to visual stimulation pre- and post- acute gabapentin administration.

Methods

Participants, males (n=16) and follicular phase females (n=16)) underwent single voxel 1H-MRS and fMRI during a single scan session in a Siemens 7T whole body MRI scanner using a vendor supplied volume coil transmit/32-Channel receive proton phased array head coil. All participants gave written informed consent for participation in this study protocol, which was approved by the Institutional Review Board at the Perelman School of Medicine of the University of Pennsylvania. GABA and Glut levels (mmol/kg brain) were measured in a 20x30x20 mm3 voxel in the visual cortex (VC; Figure 1) prior to viewing a blinking checkerboard. Mean and Max BOLD signal was determined in the spectroscopy voxel. A second identical scan paradigm was conducted 2.5 hours after oral ingestion of 900 mg of gabapentin.

Results

Mean GABA concentrations in VC were 1.13+/-0.2 and 1.30+/-0.17 mM prior to and after gabapentin administration, respectively (p<0.0001); individual changes ranged from -16% to 48%. Glut levels were steady throughout. Percent change in GABA was inversely correlated with baseline GABA levels (r= -0.673, p<0.0001; data shown separately for males and females (Figures 2A & 2B)). Similar GABA and Glut levels were observed between men and women. Among females only, max BOLD signal was reduced in VC post gabapentin administration (t=2.1, df=15, p=0.049) with a trend decrease in mean VC BOLD signal change (t=1.8, df=15, p=0.09).

Conclusions

In this 1st study of gabapentin effects on VC GABA, Glut and regional activation in a sample of males and females we have replicated our previous findings from men only suggesting that gabapentin-induced changes in brain GABA levels depend on pre-treatment GABA levels. These data suggest that there is a physiologic range in which GABA levels can be changed with drug administration. Glut levels were not significantly affected by a single dose of gabapentin. Our early findings suggest sex differences in gabapentin-induced changes in brain activation, but the relationship between GABA levels as measured using 1H-MRS and functional outcomes is complex and requires further investigation.

Acknowledgements

This project was supported by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health through Grant Number P41-EB015893 and the National Institute of Neurological Disorders and Stroke through Award Number R01NS087516 and P50 MH099910, K24 DA030301, R01 AG048839, K12 HD085848.

References

1. FDA Recommendations: Strategies for Assessing Gender Differences 12/18/2014 http://www.fda.gov/ScienceResearch/SpecialTopics/WomensHealthResearch/ucm134469.htm

2. FDA Drug Safety Communication: Risk of next-morning impairment after use of insomnia drugs; FDA requires lower recommended doses for certain drugs containing zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist) 07/16/15 http://www.fda.gov/Drugs/DrugSafety/ucm334033.htm

Figures

Anatomical slice displaying the spectroscopy voxel positioned in visual cortex (VC).

Correlation between baseline GABA levels and % change in GABA with gabapentin administration in males (A) and females (B).



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
3328