γ-Amino butyric acid and glutamate abnormalities in adolescent chronic marijuana smokers

Abstract

Background: An increasing body of evidence from neuropsychological and neuroimaging studies suggests that exposure to marijuana throughout adolescence disrupts key cortical maturation processes occurring during this developmental phase. GABA-modulating pharmacologic treatments that elevate brain GABA concentration recently have been shown to decrease withdrawal symptoms and improve executive functioning in marijuana-dependent adult subjects. The goal of this study was to investigate whether the lower ACC glutamate previously reported in adolescent chronic marijuana smokers is associated with lower ACC GABA levels.

Methods: Standard and metabolite-edited proton MRS data were acquired from adolescent marijuana users (N=13) and similarly aged non-using controls (N=16) using a clinical 3T MRI system.

Results: The adolescent marijuana-using cohort showed significantly lower ACC GABA levels (-22%, p=0.03), which paralleled significantly lower ACC glutamate levels (-14%, p=0.01). Importantly, the lower ACC GABA and glutamate levels detected in the adolescent cohort remained significant after controlling for age and sex.

Conclusions: The present spectroscopic findings support functional neuroimaging data documenting cingulate dysfunction in marijuana-dependent adolescents. Glutamatergic and GABAergic abnormalities potentially underlie cingulate dysfunction in adolescent chronic marijuana users, and the opportunity for testing suitable pharmacologic treatments with a non-invasive pharmacodynamic evaluation exists.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Figures

Fig. 1

(a) A tissue-segmented axial slice extracted from a 3D MPRAGE dataset recorded from a 17-year-old female HC subject. WM, GM and CSF are represented by white, light gray and dark gray pixels, respectively. (b) A tissue-segmented sagital slice extracted from the same MPRAGE dataset. The black rectangle depicts the positioning of the MRS voxel within the ACC, which was obliqued along the sagital dimension. For this subject, GM, WM and CSF tissue fractions were estimated to be 74, 24 and 2%, respectively.

Fig. 2

(a) and (b) show the MEGAPRESS editing pulse ‘on’ (red spectra) and ‘off’ (black spectra) condition 1H MRS spectra recorded from a HC and MJ subject, respectively. The main signals tentatively assigned in (a) and can be directly translated to (b). The resulting MEGAPRESS difference spectra are presented for the (c) HC and (d) MJ subject, which are characterized by an inverted NAA resonance at 2.0 ppm, the edited GABA peak (plus macromolecule) at 3.0 ppm and a co-edited composite Gln/Glu resonance at 3.75 ppm. The estimated GABA fits are overlaid in both MEGAPRESS GABA-edited datasets (red dashed spectra) with the direct overlay of the HC and MJ GABA fits presented in (e). This particular MJ subject showed a 17% lower CSF-corrected GABA:water ratio when compared to the HC data. The group averaged GABA fits are presented in panel (f) for both the HC (dashed line) and MJ (dotted line) cohorts. Note that the vertical scaling was increased fivefold for the MEGAPRESS-edited data in (c) and (d) whereas the vertical scaling for plots (e) and (f) was enhanced by a factor of twenty.

Fig. 3

Box plots showing the mean water-normalized GABA (left) and Glu (right) levels measured in the HC and MJ cohorts. The ■ symbol and within-box horizontal lines represent the mean and median values, respectively. The box extremities correspond to the 25th and 75th percentiles and the ‘×’ symbol represents the full data range.

Fig. 4

A plot of the water-normalized Glu versus GABA levels for all HC (unfilled squares) and MJ (filled squares) subjects. The overlaid confidence ellipse (dashed line) was computed using a 95% confidence level. The * symbols denote the two potential outliers from the HC population (see text for statistical results).