The relationship between glutamate, dopamine, and cortical gray matter: A simultaneous PET-MR study

Abstract

Prefrontal cortex has been shown to regulate striatal dopaminergic function via glutamatergic mechanisms in preclinical studies. Concurrent disruption of these systems is also often seen in neuropsychiatric disease. The simultaneous measurement of striatal dopamine signaling, cortical gray matter, and glutamate levels is therefore of major interest, but has not been previously reported. In the current study, twenty-eight healthy subjects underwent 2 simultaneous [¹¹C]-( + )-PHNO PET-MRI scans, once after placebo and once after amphetamine in a double-blind randomized cross-over design, to measure striatal dopamine release, striatal dopamine receptor (D_2/3R) availability, anterior cingulate glutamate+glutamine (Glx) levels, and cortical gray matter volumes at the same time. Voxel-based morphometry was used to investigate associations between neurochemical measures and gray matter volumes. Whole striatum D_2/3R availability was positively associated with prefrontal cortex gray matter volume (pFWE corrected = 0.048). This relationship was mainly driven by associative receptor availability (pFWE corrected = 0.023). In addition, an interaction effect was observed between sensorimotor striatum D_2/3R availability and anterior cingulate Glx, such that in individuals with greater anterior cingulate Glx concentrations, D_2/3R availability was negatively associated with right frontal cortex gray matter volumes, while a positive D_2/3R-gray matter association was observed in individuals with lower anterior cingulate Glx levels (pFWE corrected = 0.047). These results are consistent with the hypothesis that the prefrontal cortex is involved in regulation of striatal dopamine function. Furthermore, the observed associations raise the possibility that this regulation may be modulated by anterior cingulate glutamate concentrations.

Fig. 1. Positive correlation between gray matter volume of a right prefrontal cluster and dopamine receptor availability at baseline in whole striatum.

A Voxels significant at p < 0.05 (FWE corrected) shown, color bar represents T-score. B Scatter plot of gray matter density from the significant cluster against whole striatum BP_NDplacebo.

Fig. 2. Negative correlation between gray matter volume of a left orbitofrontal cluster and amphetamine-induced dopamine release in sensorimotor striatum.

A Voxels significant at p < 0.05 (FWE corrected) shown, color bar represents T-score. B Scatter plot of gray matter density from the significant cluster against sensorimotor striatum ΔBP_ND.

Fig. 3. Gray matter volume showing a negative correlation with the interaction term sensorimotor BPNDplacebo:Glx.

A Voxels significant at p < 0.05 (FWE corrected) shown, color bar represents T-score. B Median splitting was performed to graphically separate subjects with low or high Glx levels. Subjects with low Glx levels show increase in gray matter volume at voxel [54, −3, 22] along increase in sensorimotor receptor availability while subjects with high Glx levels demonstrate the inverse relationship.