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A role for neuropeptides in tardive dyskinesia : blockade of opioid and non-opioid peptide receptors suppresses neuroleptic-induced vacuous chewing movements

University of British Columbia

The treatment of schizophrenia with chronic neuroleptic therapy leads to the development of tardive dyskinesia, an involuntary movement disorder principally manifest in the orobuccal region, in approximately 20- 30 % of patients. While the pathogenesis of tardive dyskinesia remains uncertain, altered function of both opioid and non-opioid peptides in the basal ganglia has been implicated in its emergence. The levels of both the opioid peptides dynorphin and enkephalin are increased following long-term treatment with classical antipsychotic drugs. In addition, the levels of striatal neurotensin, a non-opioid peptide, are augmented following chronic neuroleptic treatment. Using a rodent model of tardive dyskinesia, vacuous chewing movements induced by chronic neuroleptic therapy, we have examined the role of these opioid and non-opioid peptides in the emergence of tardive dyskinesia. Animals received chronic administration of fluphenazine decanoate (25mg/kg i.m.) or its vehicle, sesame oil, every 3 weeks for a minimum of 18 weeks. Animals were then surgically implanted with stainless steel guide cannulae aimed at the striatum, the substantia nigra pars reticulata, or the globus pallidus. In order to examine the role of opioid peptides in tardive dyskinesia, we infused the kappa opioid receptor antagonist, nor-binaltorphimine, into the substantia nigra pars reticulata, or the nonspecific opioid antagonist, naloxone, into the globus pallidus. To further clarify the specific receptor subtypes involved, we infused D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr Amide (CTOP), a selective mu-opioid receptor antagonist, or naltrindole, a specific delta- opioid receptor antagonist, into the globus pallidus of separate groups of animals. For investigation of the role of the non-opioid peptide neurotensin in tardive dyskinesia, we infused the neurotensin antagonist 2-[(1-(7-chloro-4-qumolinyl)-5-(2,6-dimethoxyphenyl)pyrazol-3-yl)carbonylamino] tricyclo(3.3.1.1.³‧⁷) decan-2-carboxylic acid (SR48692) into the striatum, the substantia nigra pars reticulata, or the globus pallidus. Chronic treatment with fluphenazine decanoate resulted in the robust development of vacuous chewing movements. All antagonist compounds suppressed vacuous chewing movements to varying degrees, depending on the compound used and the location of infusion. These results suggest a possible role for opioid and non-opioid peptides in the emergence of tardive dyskinesia. Thus, drug treatments which reduce or prevent the effects of increased expression of these peptides may be helpful in the management of tardive dyskinesia.

Thesis/Dissertation

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2009-09-28

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http://hdl.handle.net/2429/13276

Neuroscience

University of British Columbia

UBCV

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