Development of motor side effects (e.g., acute dystonia, Parkinsonism, tardive dyskinesia) is a serious problem associated with majority of antipsychotic drugs (APDs) used for the treatment of acute and chronic psychoses. The APD-induced movement disorders are clinically indistinguishable from their idiopathic counterparts. Alterations in dopamine systems have been implicated in the etiology of these diseases since all clinically effective APDs appear to block dopamine D2 receptors. However, identification of APD's neuronal substrates postsynaptic to dopamine is necessary to gain an insight into the common pathological mechanisms which underlie APD-induced and idiopathic movement deficits. Studies from this and other laboratories have shown that only those APDs which possess a high propensity to induce motor side effects (typical APDs) appear to alter selectively expression of genes encoding, neurotensin (NT, a putative endogenous neuroleptic-like compound), fos (a purported transcription factor) or substance P (SP, another neuroactive peptide closely interacting with basal ganglia dopamine systems). Additionally, these APD-sensitive neurons were located primarily in lateral regions of the striatum which show predominantly sensorimotor connections. Our pilot studies indicated an excellent correlation (r=0.67) between APD-induced increases and tolerance in NT and c-fos gene expression in the dorsolateral striatum and induction and tolerance in cataleptic behavior (indicative of Parkinsonism) of the same animals. Acutely enhanced expression of NT gene in the dorsolateral striatum was also observed in 6-hydroxydopamine model of Parkinson's disease. Hence, I have hypothesized that alterations in the activity of dorsolateral striatal neurons expressing NT, c-fos or perhaps SP genes may be involved in APD-induced cataleptic behavior of rats. Unlike the dorsolateral changes, sustained increases in NT and c-fos gene expression in ventrolateral striatal neurons were observed after chronic blockade of dopamine transmission by the typical APD, haloperidol, or 6-hydroxydopamine. Interestingly, ventrolateral striatum appears to be involved in induction of oral movements in rats. Hence, I have hypothesized that alterations in NT and c-fos gene expression in the ventrolateral striatum may be functionally related to dystonia- or tardive dyskinesia-like oral movements in rats. This proposal includes behavioral, anatomical and neurochemical techniques to test the hypotheses listed above. The technique of in situ hybridization histochemistry will be used to study alterations in NT, c-fos an SP gene expression in discrete populations of striatal neurons in animal models of movement disorders described above. Additionally, the role of dopamine D2 receptors in the APD-mediated regulation of NT, c-fos and SP genes will be evaluated. Finally, anatomical characterization of NT and fos neurons with respect to their (a) localization in striosomal/matrix compartments, (b) co-expression of enkephalin or SP genes and (c) projection fields will be carried out. It is hoped that these studies will lead to a better understanding o neuronal pathways involved in APD- induced and idiopathic movement disorders.
| Merchant, K M (1994) c-fos antisense oligonucleotide specifically attenuates haloperidol-induced increases in neurotensin/neuromedin N mRNA expression in rat dorsal striatum. Mol Cell Neurosci 5:336-44 |
