Rats subjected to chronic treatment with neuroleptics provide a meaningful way to assess the effects of such treatment on the brain. Neuroleptic treatment in rats produces oral dyskinesias called VCMs, which mimic many of the pharmacological and phenomenological characteristics of TD. In an initial study we found that striatal synaptic density decreased in rats treated chronically with haloperidol, was more profoundly and uniquely affected in the subset of these animals with VCMs and recovered following a drug withdrawal period. Our preliminary data suggests that schizophrenics with TD show similar changes to those seen in rats with VCMs, namely fewer striatal symmetric synapses and fewer mitochondria. The overall goal of this proposal is to answer additional questions raised by the data obtained from the animal model.
The Specific Aims are as follows: 1) to confirm and extend our initial findings that haloperidol-induced VCMs are correlated with fewer symmetric synapses and mitochondrial abnormalities and to test the hypothesis that these changes are absent in rats treated with the atypical neuroleptic, clozapine, which does not cause TD or VCMs: 2) to determine, using immunocytochemical techniques, which neurochemically defined subsets of striatal terminals are affected in animals with high VCM scores and which subset(s) recover after drug withdrawal; 3) to determine if the ultrastructural correlates of VCMs in the striatum of rats treated chronically with haloperidol are attenuated by the coadministration of two GABA agonists,,just as are the behavioral manifestations; and 4) to test the hypothesis that ultrastructural changes will be present before or at the same time as VCMs by doing a time course behavioral and anatomical study. The proposed experiments will correlate VCMs and ultrastructural changes, thus determining how universal the covariance is. Moreover, the results from SA#4 may show that the ultrastructural changes precede or occur simultaneously with VCMs, suggesting causality. The results will reveal which neurochemically defined subset(s) of striatal terminals are lost in the rats with high VCMs, suggesting which circuitry is disturbed and ultimately the structural substrate of VCMs. These data may guide the discovery of new antipsychotic medications without dyskinetic side effects. These results will have implications for interpreting drug versus disease effect in data obtained from the brains of schizophrenics who died on medication.
