Neuroimaging markers of glutamatergic and GABAergic systems in drug addiction: Relationships to resting-state functional connectivity

Abstract

Drug addiction is characterized by widespread abnormalities in brain function and neurochemistry, including drug-associated effects on concentrations of the excitatory and inhibitory neurotransmitters glutamate and gamma-aminobutyric acid (GABA), respectively. In healthy individuals, these neurotransmitters drive the resting state, a default condition of brain function also disrupted in addiction. Here, our primary goal was to review in vivo magnetic resonance spectroscopy and positron emission tomography studies that examined markers of glutamate and GABA abnormalities in human drug addiction. Addicted individuals tended to show decreases in these markers compared with healthy controls, but findings also varied by individual characteristics (e.g., abstinence length). Interestingly, select corticolimbic brain regions showing glutamatergic and/or GABAergic abnormalities have been similarly implicated in resting-state functional connectivity deficits in drug addiction. Thus, our secondary goals were to provide a brief review of this resting-state literature, and an initial rationale for the hypothesis that abnormalities in glutamatergic and/or GABAergic neurotransmission may underlie resting-state functional deficits in drug addiction. In doing so, we suggest future research directions and possible treatment implications.

Keywords: Drug addiction; GABA; Glutamate; Magnetic resonance spectroscopy; Neurochemistry; Positron emission tomography; Resting-state; fMRI.

Figure 1

Overview of the MRS and PET/SPECT studies. Figure displays regions of interest common to many studies (blue: rostral/pregenual anterior cingulate cortex, sometimes extending into medial prefrontal cortex; red: dorsal anterior cingulate cortex; yellow: basal ganglia/thalamus; green: occipital cortex; pink: cerebellum; brown: insula; orange: hippocampus; purple: dorsolateral prefrontal cortex) and a table showing the general direction of effects. Arrows in the table reflect the preponderance of evidence while also prioritizing studies with larger and/or more homogeneous samples and not considering acute clinical features such as short-term withdrawal (which can be associated with opposite effects). ↓ = lower in addiction; ↑ higher in addiction; ↔ = nonsignificant differences between groups; -- no studies found.

Figure 2

Schematic of the hypothesized model. Deficits in glutamate and/or GABA, which are further modulated by clinical characteristics including withdrawal/abstinence, are associated with deficits in brain resting-state functional connectivity (e.g., anterior cingulate cortex with the dorsal and ventral striatum), which in turn are associated with drug-related symptoms. [The metabolite image (left) is adapted from (Abe et al., 2013), with permission from Elsevier; the brain image (top) is adapted from (Garland et al., 2014), under the Creative Commons Attribution License; and the drug image (right) is adapted from (Moeller et al., 2009), with permission from Elsevier].