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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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References

  • Abi-Saab WM, Bubser M, Roth RH, Deutch AY (1999) 5-HT2 receptor regulation of extracellular GABA levels in the prefrontal cortex. Neuropsychopharmacology 20:92–96

    Article  PubMed  CAS  Google Scholar 

  • Bal A, Bachelot T, Savasta M, Manier M, Verna JM, Benabid AL, Feuerstein C (1994) Evidence for dopamine D2 receptor mRNA expression by striatal astrocytes in culture: in situ hybridization and polymerase chain reaction studies. Brain Res Mol Brain Res 23:204–212

    Article  PubMed  CAS  Google Scholar 

  • Basson BR, Kinon BJ, Taylor CC, Szymanski KA, Gilmore JA, Tollefson GD (2001) Factors influencing acute weight change in patients with schizophrenia treated with olanzapine, haloperidol, or risperidone. J Clin Psychiatry 62:231–238

    Article  PubMed  CAS  Google Scholar 

  • Bernstein EM, Quick MW (1999) Regulation of gamma-aminobutyric acid (GABA) transporters by extracellular GABA. J Biol Chem 274:889–895

    Article  PubMed  CAS  Google Scholar 

  • Bourdelais AJ, Deutch AY (1994) The effects of haloperidol and clozapine on extracellular GABA levels in the prefrontal cortex of the rat: an in vivo microdialysis study. Cereb Cortex 4:69–77

    Article  PubMed  CAS  Google Scholar 

  • Bustillo J, Barrow R, Paz R, Tang J, Seraji-Bozorgzad N, Moore GJ, Bolognani F, Lauriello J, Perrone-Bizzozero N, Galloway MP (2005) Long-term treatment of rats with haloperidol: lack of an effect on brain N-acetyl aspartate levels. Neuropsychopharmacology 31:751–756

    Article  Google Scholar 

  • Bymaster FP, Calligaro DO, Falcone JF, Marsh RD, Moore NA, Tye NC, Seeman P, Wong DT (1996) Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 14:87–96

    Article  PubMed  CAS  Google Scholar 

  • Cahn W, Hulshoff Pol HE, Lems EB, van Haren NE, Schnack HG, van der Linden JA, Schothorst PF, van Engeland H, Kahn RS (2002) Brain volume changes in first-episode schizophrenia: a 1-year follow-up study. Arch Gen Psychiatry 59:1002–1010

    Article  PubMed  Google Scholar 

  • Cerdan S, Künnecke B, Seelig J (1990) Cerebral metabolism of [1,2-13C2]acetate as detected by in vivo and in vitro 13C NMR. J Biol Chem 265:12916–12926

    PubMed  CAS  Google Scholar 

  • Cozzi NV, Nichols DE (1996) 5-HT2A receptor antagonists inhibit potassium-stimulated gamma-aminobutyric acid release in rat frontal cortex. Eur J Pharmacol 309:25–31

    Article  PubMed  CAS  Google Scholar 

  • Delle Donne KT, Sesack SR, Pickel VM (1997) Ultrastructural immunocytochemical localization of the dopamine D2 receptor within GABAergic neurons of the rat striatum. Brain Res 746:239–255

    Article  PubMed  CAS  Google Scholar 

  • Dorph-Petersen KA, Pierri JN, Perel JM, Sun Z, Sampson AR, Lewis DA (2005) The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys. Neuropsychopharmacology 30:1649–1661

    Article  PubMed  CAS  Google Scholar 

  • Eastwood SL, Heffernan J, Harrison PJ (1997) Chronic haloperidol treatment differentially affects the expression of synaptic and neuronal plasticity-associated genes. Mol Psychiatr 2:322–329

    Article  CAS  Google Scholar 

  • Eloqayli H, Dahl CB, Gotestam KG, Unsgard G, Hadidi H, Sonnewald U (2003) Pentylenetetrazole decreases metabolic glutamate turnover in rat brain. J Neurochem 85:1200–1207

    Article  PubMed  CAS  Google Scholar 

  • Gao XM, Hashimoto T, Cooper TB, Tamminga CA (1997) The dose-response characteristics of rat oral dyskinesias with chronic haloperidol or clozapine administration. J Neural Transm 104:97–104

    Article  PubMed  CAS  Google Scholar 

  • Girault JA (2012) Integrating neurotransmission in striatal medium spiny neurons. Adv Exp Med Biol 970:407–429

    Article  PubMed  CAS  Google Scholar 

  • Grimm JW, See RE (2000) Chronic haloperidol-induced alterations in pallidal GABA and striatal D(1)-mediated dopamine turnover as measured by dual probe microdialysis in rats. Neuroscience 100:507–514

    Article  PubMed  CAS  Google Scholar 

  • Harsing LG Jr, Zigmond MJ (1997) Influence of dopamine on GABA release in striatum: evidence for D1–D2 interactions and non-synaptic influences. Neuroscience 77:419–429

    Article  PubMed  CAS  Google Scholar 

  • Hertz L, Zielke HR (2004) Astrocytic control of glutamatergic activity: astrocytes as stars of the show. Trends Neurosci 27:735–743

    Article  PubMed  CAS  Google Scholar 

  • Hertz L, Peng L, Dienel GA (2007) Energy metabolism in astrocytes: high rate of oxidative metabolism and spatiotemporal dependence on glycolysis/glycogenolysis. J Cereb Blood Flow Metab 27:219–249

    Article  PubMed  CAS  Google Scholar 

  • Hess EJ, Norman AB, Creese I (1988) Chronic treatment with dopamine receptor antagonists: behavioral and pharmacologic effects on D1 and D2 dopamine receptors. J Neurosci 8:2361–2370

    PubMed  CAS  Google Scholar 

  • Ho BC, Andreasen NC, Ziebell S, Pierson R, Magnotta V (2011) Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry 68:128–137

    Article  PubMed  Google Scholar 

  • Honea R, Crow TJ, Passingham D, Mackay CE (2005) Regional deficits in brain volume in schizophrenia: a meta-analysis of voxel-based morphometry studies. Am J Psychiatry 162:2233–2245

    Article  PubMed  Google Scholar 

  • Jablensky A (1997) The 100-year epidemiology of schizophrenia. Schizophr Res 28:111–125

    Article  PubMed  CAS  Google Scholar 

  • Kasper S, Lerman MN, McQuade RD, Saha A, Carson WH, Ali M, Archibald D, Ingenito G, Marcus R, Pigott T (2003) Efficacy and safety of aripiprazole vs. haloperidol for long-term maintenance treatment following acute relapse of schizophrenia. Int J Neuropsychopharmacol 6:325–337

    Article  PubMed  CAS  Google Scholar 

  • Khan ZU, Koulen P, Rubinstein M, Grandy DK, Goldman-Rakic PS (2001) An astroglia-linked dopamine D2-receptor action in prefrontal cortex. Proc Natl Acad Sci U S A 98:1964–1969

    Article  PubMed  CAS  Google Scholar 

  • Kim KS, Yoon YR, Lee HJ, Yoon S, Kim SY, Shin SW, An JJ, Kim MS, Choi SY, Sun W, Baik JH (2010) Enhanced hypothalamic leptin signaling in mice lacking dopamine D2 receptors. J Biol Chem 285:8905–8917

    Article  PubMed  CAS  Google Scholar 

  • Kondziella D, Brenner E, Eyjolfsson EM, Markinhuhta KR, Carlsson ML, Sonnewald U (2006) Glial–neuronal interactions are impaired in the schizophrenia model of repeated MK801 exposure. Neuropsychopharmacology 31:1880–1887

    Article  PubMed  CAS  Google Scholar 

  • Konopaske GT, Dorph-Petersen KA, Sweet RA, Pierri JN, Zhang W, Sampson AR, Lewis DA (2008) Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys. Biol Psychiatry 63:759–765

    Article  PubMed  CAS  Google Scholar 

  • Kuroki T, Meltzer HY, Ichikawa J (1999) Effects of antipsychotic drugs on extracellular dopamine levels in rat medial prefrontal cortex and nucleus accumbens. J Pharmacol Exp Ther 288:774–781

    PubMed  CAS  Google Scholar 

  • Le Moine C, Gaspar P (1998) Subpopulations of cortical GABAergic interneurons differ by their expression of D1 and D2 dopamine receptor subtypes. Brain Res Mol Brain Res 58:231–236

    Article  PubMed  Google Scholar 

  • Lieberman JA, Tollefson GD, Charles C, Zipursky R, Sharma T, Kahn RS, Keefe RS, Green AI, Gur RE, McEvoy J, Perkins D, Hamer RM, Gu H, Tohen M (2005) Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry 62:361–370

    Article  PubMed  CAS  Google Scholar 

  • Liegeois JF, Ichikawa J, Meltzer HY (2002) 5-HT(2A) receptor antagonism potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and inhibits that in the nucleus accumbens in a dose-dependent manner. Brain Res 947:157–165

    Article  PubMed  CAS  Google Scholar 

  • Lindefors N, Brene S, Herrera-Marschitz M, Persson H (1989a) Region specific regulation of glutamic acid decarboxylase mRNA expression by dopamine neurons in rat brain. Exp Brain Res 77:611–620

    Article  PubMed  CAS  Google Scholar 

  • Lindefors N, Brodin E, Tossman U, Segovia J, Ungerstedt U (1989b) Tissue levels and in vivo release of tachykinins and GABA in striatum and substantia nigra of rat brain after unilateral striatal dopamine denervation. Exp Brain Res 74:527–534

    Article  PubMed  CAS  Google Scholar 

  • Lipska BK, Lerman DN, Khaing ZZ, Weickert CS, Weinberger DR (2003) Gene expression in dopamine and GABA systems in an animal model of schizophrenia: effects of antipsychotic drugs. Eur J Neurosci 18:391–402

    Article  PubMed  Google Scholar 

  • Mathalon DH, Sullivan EV, Lim KO, Pfefferbaum A (2001) Progressive brain volume changes and the clinical course of schizophrenia in men: a longitudinal magnetic resonance imaging study. Arch Gen Psychiatry 58:148–157

    Article  PubMed  CAS  Google Scholar 

  • McKenna MC (2007) The glutamate-glutamine cycle is not stoichiometric: fates of glutamate in brain. J Neurosci Res 85:3347–3358

    Article  PubMed  CAS  Google Scholar 

  • Melø TM, Nehlig A, Sonnewald U (2006) Neuronal–glial interactions in rats fed a ketogenic diet. Neurochem Int 48:498–507

    Article  PubMed  Google Scholar 

  • Minet-Ringuet J, Even PC, Guesdon B, Tome D, de Beaurepaire R (2005) Effects of chronic neuroleptic treatments on nutrient selection, body weight, and body composition in the male rat under dietary self-selection. Behav Brain Res 163:204–211

    Article  PubMed  CAS  Google Scholar 

  • Momiyama T, Koga E (2001) Dopamine D(2)-like receptors selectively block N-type Ca(2+) channels to reduce GABA release onto rat striatal cholinergic interneurones. J Physiol 533:479–492

    Article  PubMed  CAS  Google Scholar 

  • Muly EC 3rd, Szigeti K, Goldman-Rakic PS (1998) D1 receptor in interneurons of macaque prefrontal cortex: distribution and subcellular localization. J Neurosci 18:10553–10565

    PubMed  CAS  Google Scholar 

  • Nagy JI, Vincent SR, Fibiger HC (1978) Altered neurotransmitter synthetic enzyme activity in some extrapyramidal nuclei after lesions of the nigro-striatal dopamine projection. Life Sci 22:1777–1782

    Article  PubMed  CAS  Google Scholar 

  • Norenberg MD, Martinez-Hernandez A (1979) Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res 161:303–310

    Article  PubMed  CAS  Google Scholar 

  • Ongur D, Prescot AP, McCarthy J, Cohen BM, Renshaw PF (2010) Elevated gamma-aminobutyric acid levels in chronic schizophrenia. Biol Psychiatry 68:667–670

    Article  PubMed  Google Scholar 

  • Osborne PG, O’Connor WT, Beck O, Ungerstedt U (1994) Acute versus chronic haloperidol: relationship between tolerance to catalepsy and striatal and accumbens dopamine, GABA and acetylcholine release. Brain Res 634:20–30

    Article  PubMed  CAS  Google Scholar 

  • Requardt RP, Wilhelm F, Rillich J, Winkler U, Hirrlinger J (2010) The biphasic NAD(P)H fluorescence response of astrocytes to dopamine reflects the metabolic actions of oxidative phosphorylation and glycolysis. J Neurochem 115:483–492

    Article  PubMed  CAS  Google Scholar 

  • Requardt RP, Hirrlinger PG, Wilhelm F, Winkler U, Besser S, Hirrlinger J (2012) Ca(2)(+) signals of astrocytes are modulated by the NAD(+)/NADH redox state. J Neurochem 120:1014–1025

    PubMed  CAS  Google Scholar 

  • Richelson E, Souder T (2000) Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds. Life Sci 68:29–39

    Article  PubMed  CAS  Google Scholar 

  • Schousboe A, Sarup A, Bak LK, Waagepetersen HS, Larsson OM (2004) Role of astrocytic transport processes in glutamatergic and GABAergic neurotransmission. Neurochem Int 45:521–527

    Article  PubMed  CAS  Google Scholar 

  • Seamans JK, Gorelova N, Durstewitz D, Yang CR (2001) Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons. J Neurosci 21:3628–3638

    PubMed  CAS  Google Scholar 

  • See RE, Chapman MA (1994) Chronic haloperidol, but not clozapine, produces altered oral movements and increased extracellular glutamate in rats. Eur J Pharmacol 263:269–276

    Article  PubMed  CAS  Google Scholar 

  • See RE, Lynch AM (1995) Chronic haloperidol potentiates stimulated glutamate release in caudate putamen, but not prefrontal cortex. Neuroreport 6:1795–1798

    Article  PubMed  CAS  Google Scholar 

  • Shirakawa O, Tamminga CA (1994) Basal ganglia GABAA and dopamine D1 binding site correlates of haloperidol-induced oral dyskinesias in rat. Exp Neurol 127:62–69

    Article  PubMed  CAS  Google Scholar 

  • Sonnewald U, Kondziella D (2003) Neuronal glial interaction in different neurological diseases studied by ex vivo 13C NMR spectroscopy. NMR Biomed 16:424–429

    Article  PubMed  CAS  Google Scholar 

  • Steulet AF, Bernasconi R, Leonhardt T, Martin P, Grunenwald C, Bischoff S, Heinrich M, Bandelier V, Maitre L (1990) Effects of selective dopamine D1 and D2 receptor agonists on the rate of GABA synthesis in mouse brain. Eur J Pharmacol 191:19–27

    Article  PubMed  CAS  Google Scholar 

  • Storey JD (2002) A direct approach to false discovery rates. J Roy Statist Soc Ser B 64:479–498

    Article  Google Scholar 

  • Theberge J, Bartha R, Drost DJ, Menon RS, Malla A, Takhar J, Neufeld RW, Rogers J, Pavlosky W, Schaefer B, Densmore M, Al-Semaan Y, Williamson PC (2002) Glutamate and glutamine measured with 4.0 T proton MRS in never-treated patients with schizophrenia and healthy volunteers. Am J Psychiatry 159:1944–1946

    Article  PubMed  Google Scholar 

  • Theberge J, Al-Semaan Y, Williamson PC, Menon RS, Neufeld RW, Rajakumar N, Schaefer B, Densmore M, Drost DJ (2003) Glutamate and glutamine in the anterior cingulate and thalamus of medicated patients with chronic schizophrenia and healthy comparison subjects measured with 4.0-T proton MRS. Am J Psychiatry 160:2231–2233

    Article  PubMed  Google Scholar 

  • Trantham-Davidson H, Neely LC, Lavin A, Seamans JK (2004) Mechanisms underlying differential D1 versus D2 dopamine receptor regulation of inhibition in prefrontal cortex. J Neurosci 24:10652–10659

    Article  PubMed  CAS  Google Scholar 

  • Vermeulen RJ, Jongenelen CA, Langeveld CH, Wolters EC, Stoof JC, Drukarch B (1994) Dopamine D1 receptor agonists display a different intrinsic activity in rat, monkey and human astrocytes. Eur J Pharmacol 269:121–125

    Article  PubMed  CAS  Google Scholar 

  • Vincent SL, Adamec E, Sorensen I, Benes FM (1994) The effects of chronic haloperidol administration on GABA-immunoreactive axon terminals in rat medial prefrontal cortex. Synapse 17:26–35

    Article  PubMed  CAS  Google Scholar 

  • von Wilmsdorff M, Bouvier ML, Henning U, Schmitt A, Gaebel W (2010) The impact of antipsychotic drugs on food intake and body weight and on leptin levels in blood and hypothalamic ob-r leptin receptor expression in wistar rats. Clinics (Sao Paulo) 65:885–894

    Article  Google Scholar 

  • Waddington JL, Gamble SJ (1980) Neuroleptic treatment for a substantial proportion of adult life: behavioural sequelae of 9 months haloperidol administration. Eur J Pharmacol 67:363–369

    Article  PubMed  CAS  Google Scholar 

  • Waniewski RA, Martin DL (1998) Preferential utilization of acetate by astrocytes is attributable to transport. J Neurosci 18:5225–5233

    PubMed  CAS  Google Scholar 

  • Waniewski RA, Martin DL (2004) Astrocytes and synaptosomes transport and metabolize lactate and acetate differently. Neurochem Res 29:209–217

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto BK, Cooperman MA (1994) Differential effects of chronic antipsychotic drug treatment on extracellular glutamate and dopamine concentrations. J Neurosci 14:4159–4166

    PubMed  CAS  Google Scholar 

  • Yamamoto BK, Pehek EA, Meltzer HY (1994) Brain region effects of clozapine on amino acid and monoamine transmission. J Clin Psychiatry 55(Suppl B):8–14

    PubMed  Google Scholar 

  • Zink M, Schmitt A, May B, Muller B, Braus DF, Henn FA (2004a) Differential effects of long-term treatment with clozapine or haloperidol on GABA transporter expression. Pharmacopsychiatry 37:171–174

    Article  PubMed  CAS  Google Scholar 

  • Zink M, Schmitt A, May B, Muller B, Demirakca T, Braus DF, Henn FA (2004b) Differential effects of long-term treatment with clozapine or haloperidol on GABAA receptor binding and GAD67 expression. Schizophr Res 66:151–157

    Article  PubMed  Google Scholar 

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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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  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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