This competitive renewal grant application proposes both laboratory and clinical research projects to follow up and continue a productive line of research in neuroleptic-induced dyskinesia pathophysiology and GABA- mediated neuronal transmission. Our findings to date have led us to formulate a """"""""working"""""""" hypothesis of neuroleptic-induced dyskinesia pathophysiology in haloperidol treated animals. We currently aim to test this idea further in rats and to explore this mechanism in schizophrenic patients with TD. Eventually, this could lead to an understanding of the pathophysiology of tardive dyskinesia (TD) and provide a small animal dyskinesia screen for new antipsychotic drugs. In addition, we have demonstrated a therapeutic effect of clozapine in TD and now are seeking to understand whether clozapine improves dyskinesias in TD through diminishing these same neuroleptic-induced GABAergic changes in the substantia nigra pars reticulata (SNR) and whether other clozapine-like antipsychotic drugs will also treat tardive dyskinesia. In this grant, we propose to pharmacologically test our """"""""working"""""""" hypothesis for the mechanism of haloperidol-induced rat oral dyskinesias. This hypothesis suggests that in rats with oral dyskinesias (not in nondyskinetic animals) an elevated dendritic release of dopamine in the SNR releases GABA from striatonigral GABA-containing neurons at a presynaptic D1 receptor to overinhibit the GABA/A receptor-bearing GABAergic nigral efferent neurons which project to thalamus. Also, we propose to evaluate new (ie """"""""atypical"""""""") neuroleptics in the rat oral dyskinesia """"""""model"""""""" we have developed, for their association with oral dyskinesias in rats. In clinical studies, we propose to test the new antipsychotic drug olanzepine for efficacy in schizophrenia with tardive dyskinesia, using the design with which we showed a therapeutic action of clozapine in TD. And, in clinical postmortem study, we propose to further evaluate our working hypothesis of tardive dyskinesia pathophysiology; here we will examine measures of dopaminergic and GABAergic transmission in basal ganglia postmortem tissue from schizophrenic patients with and without TD using similar biochemical markers as were positive in our animal dyskinesia studies. We propose that these studies will help advance our overall goals of understanding-the mechanism of -TD and developing treatments for-the disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH037073-16
Application #
2674806
Study Section
Special Emphasis Panel (SRCM (07))
Project Start
1987-09-15
Project End
2000-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
16
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Psychiatry
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Gao, Xue-Min; Cooper, Thomas; Suckow, Raymond F et al. (2006) Multidose risperidone treatment evaluated in a rodent model of tardive dyskinesia. Neuropsychopharmacology 31:1864-8
Tamminga, C A (1998) Schizophrenia and glutamatergic transmission. Crit Rev Neurobiol 12:21-36
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Roberts, R C; Gaither, L A; Gao, X M et al. (1995) Ultrastructural correlates of haloperidol-induced oral dyskinesias in rat striatum. Synapse 20:234-43
Shirakawa, O; Tamminga, C A (1994) Basal ganglia GABAA and dopamine D1 binding site correlates of haloperidol-induced oral dyskinesias in rat. Exp Neurol 127:62-9
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Cassady, S L; Thaker, G K; Tamminga, C A (1993) Pharmacologic relationship of antisaccade and dyskinesia in schizophrenic patients. Psychopharmacol Bull 29:235-40
Cassady, S L; Thaker, G K; Moran, M et al. (1992) GABA agonist-induced changes in motor, oculomotor, and attention measures correlate in schizophrenics with tardive dyskinesia. Biol Psychiatry 32:302-11
Thaker, G K; Ellsberry, R; Moran, M et al. (1991) Tobacco smoking increases square-wave jerks during pursuit eye movements. Biol Psychiatry 29:82-8

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