Chronic cocaine exposure induces putamen glutamate and glutamine metabolite abnormalities in squirrel monkeys

Abstract

Rationale: Chronic cocaine exposure has been associated with progressive brain structural and functional changes. Clarifying mechanisms underlying cocaine's progressive brain effects may help in the development of effective cocaine abuse treatments.

Objectives: We used a controlled squirrel monkey model of chronic cocaine exposure (45 mg/kg/week for 9 months) combined with ultra-high magnetic field (9.4 T) proton magnetic resonance spectroscopy to prospectively measure putamen metabolite changes.

Methods: Proton metabolites were measured with a STEAM sequence, quantified with LCModel using a simulated basis set, and expressed as metabolite/total creatine (tCr) ratios.

Results: We found cocaine-induced time-dependent changes in putamen glutamate/tCr and glutamine/tCr metabolite ratios suggestive of altered glutamate compartmentalization, neurotransmission, and metabolism. By contrast, saline-treated monkeys exhibited no metabolite changes over time. The time course of cocaine-induced metabolite abnormalities we detected is consistent with the apparent time course of glutamate abnormalities identified in a cross-sectional study in human cocaine users, as well as with microdialysis findings in rodent models of repeated cocaine exposure.

Conclusions: Together, these findings suggests that this squirrel monkey model may be useful for characterizing glutamatergic changes associated with cocaine exposure and for determining efficacies of treatments designed to mitigate cocaine-induced glutamatergic system dysfunction.

Fig. 1

A typical proton spectrum (with no line broadening) is shown. Metabolites highlighted are myo-inositol (Ins), choline-containing compounds (Cho), total creatine (tCr = phosphocreatine (PCr) + creatine (Cr)), Glutamine (Gln), Glutamate (Glu), γ-aminobutyric acid (GABA), and N-acetylaspartate (NAA). The red trace shows the LCModel fit of the data

Fig. 2

Time courses of Glu/tCr and Gln/tCr metabolite ratios in monkeys administered saline (N=4) and cocaine (N=4). Shown are means and standard errors of the mean. Post-hoc pair-wise two-sided t test contrasts legend: ***P<0.005 vs. cocaine group baseline; *P<0.05 vs. cocaine group baseline; †††P< 0.005 vs. saline group baseline; +++P<0.01 vs. saline group 9-month measurement; +P<0.05 vs. saline group 9-month measurement