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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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Neurological Disorders Program Project Review B Committee (NSPB)
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Pranzatelli, M R; Durkin, M M; Farmer, M (1996) Plastic responses of neonatal 5-hydroxytryptamine1B receptors to 5,7-dihydroxytryptamine lesions mapped by quantitative autoradiography. Int J Dev Neurosci 14:621-9
Pranzatelli, M R; Durkin, M M; Barkai, A I (1994) Quantitative autoradiography of 5-hydroxytryptamine1A binding sites in rats with chronic neonatal 5,7-dihydroxytryptamine lesions. Brain Res Dev Brain Res 80:1-6
Pranzatelli, M R; Razi, P (1994) Drug-induced regulation of [125I]iodocyanopindolol-labeled 5-hydroxytryptamine1B receptor binding sites in the central nervous system. Neuropsychopharmacology 10:259-64
Pranzatelli, M R; Tailor, P T; Pluchino, R et al. (1994) p,p'-DDT myoclonic/epileptic model: serotonin receptor binding and behavioral studies in the rat. Neurotoxicology 15:261-72
Pranzatelli, M R; Gregory, C M (1993) High and low affinity 5-HT2 and 5-HT1C binding sites: responses to neonatal 5,7-DHT lesions in rat brain. Cytobios 75:197-209
Pranzatelli, M R; Murthy, J N; Tailor, P T (1993) Novel regulation of 5-HT1C receptors: down-regulation induced both by 5-HT1C/2 receptor agonists and antagonists. Eur J Pharmacol 244:1-5
Pranzatelli, M R (1992) Serotonin receptor ontogeny: effects of agonists in 1-day-old rats. Pharmacol Biochem Behav 43:1273-7
Pranzatelli, M R; Tkach, K (1992) Regional glycine receptor binding in the p,p'-DDT myoclonic rat model. Arch Toxicol 66:73-6
Murthy, J N; Pranzatelli, M R (1992) Brainstem 5-hydroxytrytamine1A binding sites are not down-regulated by agonists which induce tolerance in the rat: myoclonus and other serotonergic behaviors. J Recept Res 12:287-97
Pranzatelli, M R; Martens, J M (1992) Plasticity and ontogeny of the central 5-HT transporter: effect of neonatal 5,7-dihydroxytryptamine lesions in the rat. Brain Res Dev Brain Res 70:191-5

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