This application proposes to examine the hypothesis that some human myoclonic disorders are associated with a dysfunction of central serotonin (5-HT) receptors. such receptor abnormalities, acquired genetically or in response to brain injury, may be pharmacologically treatable. This hypothesis is based on abnormal CSF 5-HT metabolite levels and beneficial clinical response to treatment with the 5-HT precursor, 5- hydroxytryptophan (5-HTP). Other supporting evidence comes from animal models in which 5-HTP either evokes or ameliorates myoclonus. The DHT model, a proposed model of denervation supersensitivity of central 5-HT receptors, will be used to study receptor mechanisms in response to injury. We will use quantitative autoradiography to define and localize the 5-HT receptors associated with myoclonus evoked by 5-HTP in rats treated with intracisternal 5, 7-dihydroxytryptamine (DHT). Based on previous lesion studies and human pathology, we will focus on brainstem loci, especially the nucleus gigantocellularis reticularis and the inferior olive, and on the cerebellar dentate nucleus. We will identify 5-HT-1A, 5-HT-1B, 5-HT-1C, and 5-HT-2 receptors using radioligands for 5-HT receptors as described in the literature definitionally. The time course of development of receptor abnormalities will be compared to that for development of myoclonus, which will be both automatically and observer scored. The responses of 5-HT receptors to DHT in neonatal and adult rats will be compared to determine if """"""""sprouting"""""""" of 5-HT terminals in brainstem found only after neonatal DHT involves a different 5-HT receptor response to injury. To demonstrate the functional significance of DHT-induced receptor changes, we will reduce or increase myoclonus in adult DHT-treated rats by chronic treatments with serotonergic drugs known to selectively alter the 5-HT receptor abnormality we find. Myoclonic response will be correlated with modulation of 5-HT receptors at myoclonic loci as determined by quantitative autoradiography. In rats treated as neonates with DHT, we will determine if 5-HTP induces myoclonus. These parallel studies will be used to explore how pharmacologic modification of the receptor response to injury in central 5-HT systems might be used therapeutically to facilitate recovery and reduce myoclonus. They will also show how 5-HT denervation alters the regulation of central 5-HT receptors. Successful application of the quantitative autoradiographic technique in the DHT model will prepare the investigator for future human postmortem studies in myoclonic disorders.
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