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Time-dependent effects of haloperidol on glutamine and GABA homeostasis and astrocyte activity in the rat brain

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Abstract

Rationale

Schizophrenia is a severe, persistent, and fairly common mental illness. Haloperidol is widely used and is effective against the symptoms of psychosis seen in schizophrenia. Chronic oral haloperidol administration decreased the number of astrocytes in the parietal cortex of macaque monkeys (Konopaske et al., Biol Psych 63:759–765, 2008). Since astrocytes play a key role in glutamate metabolism, chronic haloperidol administration was hypothesized to modulate astrocyte metabolic function and glutamate homeostasis.

Objectives

This study investigated the effects of chronic haloperidol administration on astrocyte metabolic activity and glutamate, glutamine, and GABA homeostasis.

Methods

We used ex vivo 13C magnetic resonance spectroscopy along with high-performance liquid chromatography after [1-13C]glucose and [1,2-13C]acetate administration to analyze forebrain tissue from rats administered oral haloperidol for 1 or 6 months.

Results

Administration of haloperidol for 1 month produced no changes in 13C labeling of glutamate, glutamine, or GABA, or in their total levels. However, a 6-month haloperidol administration increased 13C labeling of glutamine by [1,2-13C]acetate. Moreover, total GABA levels were also increased. Haloperidol administration also increased the acetate/glucose utilization ratio for glutamine in the 6-month cohort.

Conclusions

Chronic haloperidol administration in rats appears to increase forebrain GABA production along with astrocyte metabolic activity. Studies exploring these processes in subjects with schizophrenia should take into account the potential confounding effects of antipsychotic medication treatment.

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Acknowledgments

This study was supported by funds from the Maria Lorenz Pope Fellowship, Harvard Medical School (GTK), 1K08MH087640-01A1 (GTK) and 5R01MH51290-08 (JTC). The authors thank Dr. Dost Öngür for the technical advice and to Susan Konopaske for reviewing the manuscript.

Conflict of interest

Glenn T. Konopaske, Nicolas Bolo, and Alo C. Basu have no conflict of interest to declare. Perry F. Renshaw has served as a consultant to Kyowa Hakko Kirin, Ridge Diagnostics, Roche, GlaxoSmithKline, and Novartis and has received research support from Roche, Eli Lilly, and GlaxoSmithKline. Joseph T. Coyle has received consulting fees from Abbott, Janssen, Eli Lilly, PureTech, EnVivo, and Sage.

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Authors and Affiliations

  1. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    Glenn T. Konopaske, Nicolas R. Bolo, Alo C. Basu, Perry F. Renshaw & Joseph T. Coyle

  2. Department of Psychiatry, University of Utah, Salt Lake City, UT, USA

    Perry F. Renshaw

  3. McLean Hospital, 115 Mill Street, MS 124, Belmont, MA, 02478, USA

    Glenn T. Konopaske

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  1. Glenn T. Konopaske
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  2. Nicolas R. Bolo
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  3. Alo C. Basu
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  5. Joseph T. Coyle
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Correspondence to Glenn T. Konopaske.

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The animals experiments conducted in this study are in compliance with applicable state and federal (USA) regulations.

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Konopaske, G.T., Bolo, N.R., Basu, A.C. et al. Time-dependent effects of haloperidol on glutamine and GABA homeostasis and astrocyte activity in the rat brain. Psychopharmacology 230, 57–67 (2013). https://doi.org/10.1007/s00213-013-3136-3

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