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

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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.

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Acknowledgments

This project was supported in part by the Counter-Drug Technology Assessment Center (CTAC), an office within the Office of National Drug Control Policy (ONDCP), via Contract Number DABK39-03-C-0075 awarded by the Army Contracting Agency. The content of the information does not necessarily reflect the position or the policy of the Government and no official endorsement should be inferred. This project also was sponsored in part by NIH grants S10RR019356, R01DA09448, and K02DA017324, by a grant from Varian, Inc., and by gifts from John and Virginia B. Taplin. We thank Nicolas Bolo, Amy C. Janes, and Bonnie Adams for their assistance with this study.

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Authors and Affiliations

  1. Brain Imaging Center, McLean Hospital, Harvard Medical School, 115 Mill, St. Belmont, MA, 02478, USA

    Xiaoxu Liu, J. Eric Jensen, Timothy E. Gillis, Chun S. Zuo, Andrew P. Prescot, Melanie Brimson, Kenroy Cayetano, Perry F. Renshaw & Marc J. Kaufman

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  1. Xiaoxu Liu
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  2. J. Eric Jensen
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  3. Timothy E. Gillis
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  4. Chun S. Zuo
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  6. Melanie Brimson
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  7. Kenroy Cayetano
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  8. Perry F. Renshaw
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  9. Marc J. Kaufman
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Correspondence to Marc J. Kaufman.

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Liu, X., Jensen, J.E., Gillis, T.E. et al. Chronic cocaine exposure induces putamen glutamate and glutamine metabolite abnormalities in squirrel monkeys. Psychopharmacology 217, 367–375 (2011). https://doi.org/10.1007/s00213-011-2292-6

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  • DOI: https://doi.org/10.1007/s00213-011-2292-6

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