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
abound
1,2. 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 mm
3 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 1
st 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