Despite the tremendous beneficial impact which the introduction of antipsychotic drugs (APD) had on the treatment of schizophrenia, these drugs are not without serious side effects. These include several neurological symptoms of which the most severe is tardive dyskinesia (TD). This syndrome, characterized by involuntary orofacial dyskinesia becomes more severe by drug withdrawal and by antimuscarinic drugs and most disturbingly, is irreversible in the majority of affected patients. This complication of long-term antipsychotic drug treatment has eluded satisfactory treatment. Based on animal experimentation in our laboratories and on some well known clinical observations, we have postulated and obtained preliminary data to support the idea that persistent TD is a result of striatal muscarinic receptor densitization which develops late during long term treatment with APD. It is hypothesized that this cholinergic alteration impedes homeostatic mechanisms (nigrostriatal neuronal loop) which are operative under basal conditions and early during APD treatment and that the magnitude of the resultant DA/ACh receptor imbalance determines the TD liability of the particular APD. This proposal aims to test this hypothesis, to explore new potential treatment strategies for TD and to develop an animal model which mimics the characteristics of the syndrome more closely than previous models which were based on dopamine receptor supersensitivity. The effect of long-term treatments with APD which possess varying degrees of TD-inducing liabilities on striatal dopamine and cholinergic muscarinic receptor binding and functional/behavioral parameters will be assessed. In addition, chronic antimuscarinic treatment will be tested for its potential in preventing the APD induced cholinergic desensitization. Experiments are also aimed at understanding the mechanisms involved in eliciting APD-induced muscarinic receptor changes. The effects of long-term APD on striatal ACh release and its modulation by presynaptic muscarinic receptors, the interaction between D1/D2 dopamine receptors on cAMP generation and the muscarinic modulation of striatal DA-activated adenylate cyclase, will be assessed. A novel animal model for TD, based on desensitizing muscarinic receptors via chronic treatment with pilocarpine will also be tested. These experiments should increase our understanding of the pathophysiology of TD and may provide new strategies for testing potential therapies for TD, chorea and Gilles de la Tourette syndrome.
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| Undie, A S; Friedman, E (1990) Stimulation of a dopamine D1 receptor enhances inositol phosphates formation in rat brain. J Pharmacol Exp Ther 253:987-92 |
