The Impact of Gabapentin Administration on Brain GABA and Glutamate Concentrations: A 7T 1H-MRS Study

Abstract

Gamma-aminobutyric acid (GABA) and glutamate are implicated in numerous neuropsychiatric and substance abuse conditions, but their spectral overlap with other resonances makes them a challenge to quantify in humans. Gabapentin, marketed for the treatment of seizures and neuropathic pain, has been shown to increase in vivo GABA concentration in the brain of both rodents and humans. Gabapentin effects on glutamate are not known. We conducted a gabapentin (900 mg) challenge in healthy human subjects to confirm and explore its effects on GABA and glutamate concentrations, respectively, and to test the ability of single voxel localized proton magnetic resonance spectroscopy ( 1 H-MRS) to reliably measure GABA and glutamate in the visual cortex at the ultra-high magnetic field of 7 Tesla. Reproducibility of GABA and glutamate measurements was determined in a comparison group without drug twice within day and 2 weeks apart. Although GABA concentration changes were small both within day (average 5.6%) and between day (average 4.8%), gabapentin administration was associated with an average increase in GABA concentration of 55.7% (6.9-91.0%). Importantly, druginduced change in GABA levels was inversely correlated to the individual's baseline GABA level (R 2 ¼ 0.72). Mean glutamate concentrations did not change significantly with or without drug administration. In conclusion, localized 1 H-MRS at 7 Tesla can be successfully applied to the measurement of GABA concentration and is sensitive to acute drug-induced changes in cortical GABA. Whether baseline GABA concentrations predict clinical efficacy of gabapentin is an area worthy of exploration.

Misuse and Abuse of Pregabalin and Gabapentin: Cause for Concern?

“…In contrast with this, however, some of the issues identified here may be a cause for concern, and these include: the complex gabapentinoid pharmacodynamics, possibly including the involvement of drug reward pathways [22]; the increasing prescription levels over time [8]; the misusers' perceptions for these molecules to constitute a valid substitute for most common illicit drugs [33]; and the increasing levels of associated fatalities from a range of countries [11]. Overall, gabapentinoid experimenters are profiled here as individuals with a history of recreational polydrug misuse [46] who self-administer with dosages clearly in excess (e.g.…”

“…Gabapentin may exert its GABAergic effects through both modulation of GABA metabolism and reversal of neuronal/ glial amino acid transporters, with GABA being released for interaction with extra-synaptic GABA receptors [20,21]. Indeed, gabapentin 900-mg administration to healthy human subjects resulted in an average increase in GABA concentration of about 56 % (6.9-91.0 %), with druginduced changes in GABA levels being inversely correlated to the individual's baseline GABA levels [22]. Finally, it has been hypothesized that both gabapentin [22] and pregabalin [23] may somehow present with direct/ indirect effects on the dopaminergic 'reward' system, effects that are typically associated with drugs' addictive liability levels [24].…”

“…Indeed, gabapentin 900-mg administration to healthy human subjects resulted in an average increase in GABA concentration of about 56 % (6.9-91.0 %), with druginduced changes in GABA levels being inversely correlated to the individual's baseline GABA levels [22]. Finally, it has been hypothesized that both gabapentin [22] and pregabalin [23] may somehow present with direct/ indirect effects on the dopaminergic 'reward' system, effects that are typically associated with drugs' addictive liability levels [24]. At dosages exceeding the therapeutic dosages, gabapentinoids, different from clonazepam (e.g.…”

Lisdexamfetamine Effects on Executive Activation and Neurochemistry in Menopausal Women with Executive Function Difficulties

“…Automated shimming of the B 0 field was performed on the voxel to obtain localized water line width of~20 Hz or less using FASTMAP. Variable power RF pulses with optimized relaxation delays (Tkac et al, 1999) were used to obtain water suppression spectra (Cai et al, 2012). SVS for Glx was obtained using short TE SVS with modified point-resolved spectroscopy sequence (PRESS) having the following parameters: spectral width = 4 kHz, number of points = 2048, averages = 16 (water reference) or 64 (water suppressed), TE = 20 ms, TR = 3000 ms. Chemical shift artifact for Glx was minimized by setting water acquisition spectrum excitation and refocusing pulses in resonance with the water peak at 4.7 p.p.m., and also setting water-suppressed spectrum excitation and refocusing pulses in resonance with the Glx peak at 2.35 p.p.m.…”

“…Using a fitting method validated by Cai et al (2012), metabolite peaks from water-suppressed spectrum were fitted as Lorentzian functions with nonlinear least squares fitting using lsqcurvefit in MATLAB. This procedure accounted for amplitudes, line widths, and peak positions for 8 macromolecular and 14 metabolite peaks.…”