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Neuropsychopharmacology (1996) 15 424-428.
Effects of Chronic Haloperidol on Stress- and Stimulation-Induced Increases in Dopamine Release: Tests of the Depolarization Block Hypothesis
Mark A Klitenick Ph.D, Matthew T Taber BA and H Christian Fibiger Ph.D |
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From the Division of Neurological Sciences, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada
Correspondence: H C Fibiger, Division of Neurological Sciences, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada
Trophix Pharmaceuticals, Inc., 40 Cragwood Road-Suite B, South Plainfield, NJ 07080
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ABSTRACT
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There is considerable neurophysiological evidence that chronically administered neuroleptics can, under certain circumstances, decrease the activity of mesencephalic dopaminergic neurons. This finding, referred to as depolarization inactivation or depolarization block, has led to the hypothesis that the delayed therapeutic effects of neuroleptic drugs are due to a gradual silencing of mesolimbic dopaminergic neurons. One prediction of depolarization inactivation is that dopamine neurons in this state should be resistant to activation by excitatory stimuli. As a test of this prediction, rats that had been treated chronically with either saline or haloperidol (0.5 mg/kg ´ 21 days) were exposed to either acute mild stress or electrical stimulation of the prelimbic region of the prefrontal cortex while extracellular levels of dopamine in the nucleus accumbens were monitored by in vivo microdialysis. A 10-minute exposure to acute stress via tail pinch increased dopamine release by 20% and 18% in the saline and haloperidol groups, respectively. Similarly, 20 minutes of cortical stimulation increased dopamine release by 51% and 56% in rats treated chronically with saline or haloperidol, respectively. These results indicate that contrary to a prediction of the depolarization block hypothesis, mesolimbic dopaminergic neurons can be activated in neuroleptic-treated animals.
Keywords: Depolarization block; Dopamine; Electrical stimulation; Prefrontal cortex; Nucleus accumbens; Schizophrenia; Stress |
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