Abstract
Prescription psychostimulants produce rapid changes in mood, energy, and attention. These drugs are widely used and abused. However, their effects in human neocortex on glutamate and glutamine (pooled as Glx), and key neurometabolites such as N-acetylaspartate (tNAA), creatine (tCr), choline (Cho), and myo-inositol (Ins) are poorly understood. Changes in these compounds could inform the mechanism of action of psychostimulant drugs and their abuse potential in humans. We investigated the acute impact of two FDA-approved psychostimulant drugs on neurometabolites using magnetic resonance spectroscopy (1H MRS). Single clinically relevant doses of d-amphetamine (AMP, 20 mg oral), methamphetamine (MA, 20 mg oral; Desoxyn®), or placebo were administered to healthy participants (n = 26) on three separate test days in a placebo-controlled, double-blinded, within-subjects crossover design. Each participant experienced all three conditions and thus served as his/her own control. 1H MRS was conducted in the dorsal anterior cingulate cortex (dACC), an integrative neocortical hub, during the peak period of drug responses (140–150 m post ingestion). D-amphetamine increased the level of Glu (p = .0001), Glx (p = .003), and tCr (p = .0067) in the dACC. Methamphetamine increased Glu in females, producing a significant crossover interaction pattern with gender (p = .02). Drug effects on Glu, tCr, and Glx were positively correlated with subjective drug responses, predicting both the duration of AMP liking (Glu: r = +.49, p = .02; tCr: r = +.41, p = .047) and the magnitude of peak drug high to MA (Glu: r = +.52, p = .016; Glx: r = +.42, p = .049). Neither drug affected the levels of tNAA, Cho, or Ins after correction for multiple comparisons. We conclude that d-amphetamine increased the concentration of glutamate, Glx, and tCr in the dACC in male and female volunteers 21/2 hours after drug consumption. There was evidence that methamphetamine differentially affects dACC Glu levels in women and men. These findings provide the first experimental evidence that specific psychostimulants increase the level of glutamatergic compounds in the human brain, and that glutamatergic changes predict the extent and magnitude of subjective responses to psychostimulants.
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Acknowledgments
We thank Lynn Fanella, Erica Nixon, and Marilena DeMayo of the Brown University Magnetic Resonance Facility for technical assistance; Tim Souza for assistance with data processing; and Mikalei Gordon, Selen Senocak, and Nikitha Gangasani for assistance in 1H MRS data collection. The authors are entirely responsible for the scientific content of the paper.
Funding
This work was supported by the National Institute of Health Grant DA029189 (T.L.W.); National Science Foundation Graduate Research Fellowship DGE1058262 (A.Z.N.); UTRA undergraduate teaching and research award from Brown University (C.A.B., T.L.W.); National Institute of Health Training Grant AA007459 and career award K23-AA024704 (M.A.M.); National Institute of General Medical Sciences, National Institutes of Health (P20GM103645); National Institute of Health career award K01-AG050707 (A.J.W.); the National Center for Advancing Translational Sciences of the National Institutes of Health under University of Florida Clinical and Translational Science Awards KL2TR001429 and UL1TR001427; and National Institute of Health Grant AA007459. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs, United States government, National Institute of Health or National Science Foundation.
Author contributions
T.L.W. conceived the basic idea, initiated, designed, and directed the study and wrote the manuscript. T.L.W., C.A.B., A.Z.N., and E.G.W. designed procedures for voxel placement. C.A.B. and A.Z.N. acquired the majority of the MRS data. A.D.H. and E.C.P. designed and conducted the segmentation analysis for neuroanatomical data sets. E.G.W., M.A.M., A.J.W., and E.C.P. conducted the data quality control procedures. E.G.W., M.A.M., D.G.L., and T.L.W. performed the statistical and data analyses. E.C.P., A.J.W., A.D.H., R.A.C., T.L.W., S.F., D.G.L., E.G.W., and M.A.M. provided input on data analysis and the interpretation of results. T.L.W., A.D.H., M.A.M., E.C.P., S.F., D.G.L., A.J.W., R.A.C., and E.G.W. revised the manuscript. All authors read and approved the final manuscript.
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BPSsystolic blood pressure, BPD diastolic blood pressure, HR heart rate, AMP d-amphetamine, MA methamphetamine, PBO placebo
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White, T.L., Monnig, M.A., Walsh, E.G. et al. Psychostimulant drug effects on glutamate, Glx, and creatine in the anterior cingulate cortex and subjective response in healthy humans. Neuropsychopharmacol 43, 1498–1509 (2018). https://doi.org/10.1038/s41386-018-0027-7
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DOI: https://doi.org/10.1038/s41386-018-0027-7
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