Chronic haloperidol, but not clozapine, produces altered oral movements and increased extracellular glutamate in rats

https://doi.org/10.1016/0014-2999(94)90722-6Get rights and content

Abstract

Rats administered chronic haloperidol or clozapine in their drinking water for 6 months were monitored for changes in oral movements using a computerized video analysis system. Haloperidol-treated animals exhibited late onset increases in small amplitude oral movements and an increase in the percentage of oral movements in the 1–2 Hz range, accompanied by a decrease in oral movements in the higher frequency range (> 6 Hz) as determined by fast fourier analysis. In contrast, clozapine-treated rats showed a decrease in medium-sized amplitude oral movements, but did not demonstrate significant changes in the distribution of oral movements across frequencies. Extracellular concentrations of γ-aminobutyric acid (GABA) and glutamate in the ventrolateral striatum were then assessed by intracranial microdialysis during oral drug administration and 3 days after drug withdrawal. Extracellular GABA and glutamate levels were not significantly different between groups during drug administration. However, 3 days after drug withdrawal, there was a significant increase in glutamate in the haloperidol-treated rats. No changes were noted for glutamate levels in clozapine-treated rats or for GABA levels in either group following withdrawal. These results confirm the atypical profile of clozapine in an animal model of tardive dyskinesia and suggest that alterations in striatal glutamatergic function follow typical, but not atypical, antipsychotic drug administration.

References (51)

  • R.E. See et al.

    Comparison of chronic administration of haloperidol and the atypical neuroleptics, clozapine and raclopride, in an animal model of tardive dyskinesia

    Eur. J. Pharmacol.

    (1990)
  • R.E. See et al.

    Chronic neuroleptic treatment in rats produces persisting changes in GABAA and dopamine D-2, but not dopamine D-1 receptors

    Life Sci.

    (1989)
  • R.E. See et al.

    Chronic neuroleptic administration decreases extracellular GABA in the nucleus accumbens but not in the caudate-putamen of rats

    Brain Res.

    (1992)
  • R.E. See et al.

    Regional differences in chronic neuroleptic effects on extracellular dopamine activity

    Brain Res. Bull.

    (1992)
  • T. Sunderland et al.

    Blood to brain distribution of neuroleptics

    Psychiat. Res.

    (1987)
  • J.L. Waddington

    Schizophrenia, affective psychoses, and other disorders treated with neuroleptic drugs: the enigma of tardive dyskinesia, its neurobiological determinants, and the conflict of paradigms

    Int. Rev. Neurobiol.

    (1989)
  • M.P. Caligiuri et al.

    Instrumental assessment of lingual motor instability in tardive dyskinesia

    Neuropsychopharmacology

    (1989)
  • D.E. Casey

    Tardive dyskinesia

  • D.E. Casey

    Clozapine: neuroleptic-induced EPS and tardive dyskinesia

    Psychopharmacology

    (1989)
  • J. Claghorn et al.

    The risks and benefits of clozapine versus chlorpromazine

    J. Clin. Psychopharmacol.

    (1987)
  • J.T. Coyle et al.

    Oxidative stress, glutamate, and neurodegenerative disorders

    Science

    (1993)
  • J. De Keyser

    Excitotoxic mechanisms may be involved in the pathophysiology of tardive dyskinesia

    Clin. Neuropharmacol.

    (1991)
  • J.M. Delfs et al.

    Opposite effects of short and long-term haloperidol treatment on levels of mRNA encoding glutamic acid decarboxylase (GAD 67) in rat globus pallidus

    The Physiologist

    (1993)
  • B.A. Donzanti et al.

    Extracellular glutamate levels increase with age in the lateral striatum: potential involvement of presynaptic D-2 receptors

    Synapse

    (1993)
  • G.D. Ellison et al.

    Rats administered chronic neuroleptics develop oral movements which are similar in form to those in humans with tardive dyskinesia

    Psychopharmacology

    (1989)
  • Cited by (83)

    • Antipsychotic treatment leading to dopamine supersensitivity persistently alters nucleus accumbens function

      2015, Neuropharmacology
      Citation Excerpt :

      Finally, glutamate modulates dopamine function, and chronic exposure to typical versus atypical antipsychotics can evoke different neuroadaptations within the glutamate system. Chronic exposure to HAL but not to the atypical antipsychotic clozapine enhances basal extracellular glutamate levels in the striatum (See and Chapman, 1994; Yamamoto and Cooperman, 1994). In addition, chronic exposure to HAL versus to OLZ or clozapine has differential effects on the density of the NR1 subunit of the NMDA receptor in the striatum (Fitzgerald et al., 1995), and on the density of type II metabotropic glutamate receptors in the frontal cortex (Tascedda et al., 2001).

    • Antipsychotic medications, glutamate, and cell death: A hidden, but common medication side effect?

      2013, Medical Hypotheses
      Citation Excerpt :

      In summary, elevated extracellular glutamate levels have been consistently observed in caudate, frontal cortex, and nucleus accumbens in rats treated chronically with the typical antipsychotic medication haloperidol, but not with the atypical antipsychotic medication clozapine. In contrast to effects of typical antipsychotic medications on extracellular glutamate, multiple studies have demonstrated that the atypical antipsychotic medication clozapine does not affect extracellular glutamate in stratum or frontal cortex [15–17,20]. However, widespread clinical use of clozapine is limited because of metabolic side effects and risk of agranulocytosis.

    • Less Is More: Antipsychotic Drug Effects Are Greater with Transient Rather Than Continuous Delivery

      2008, Biological Psychiatry
      Citation Excerpt :

      However, chronic haloperidol treatment (either via minipump, the drinking water, or daily SC injection) decreases striatal dopamine levels (15,37–41), suggesting that nondopaminergic mechanisms might be involved. One candidate is glutamate, which remains elevated in the striatum during chronic haloperidol treatment (42–44) and is involved in antipsychotic-induced striatal c-fos expression (45–47). Whatever the underlying mechanisms, the positive correlation between c-fos mRNA expression and antipsychotic efficacy suggests that gene regulation might be a step in a chain of intracellular events that contribute to and/or maintain antipsychotic efficacy over time.

    View all citing articles on Scopus
    View full text