31 - Plasticity Responses After Neonatal Dopamine Lesions Induced With 6-Hydroxydopamine

Abstract

Selective lesions of mesencephalic dopamine neurons in newborn rats do not lead to the loss of motor function and feeding ability that is seen after similar lesions in adult rats. On the other hand, neonatal dopamine lesions induce changes that mimic certain aspects of the attention deficit and hyperactivity disorder, the Lesch–Nyhan syndrome as well as schizophrenia, e.g., locomotor hyperactivity, cognitive deficits and self-mutilation. A permanent and extensive loss of the nigrostriatal dopamine neurons is seen after neonatal intracerebral 6-hydroxydopamine administration, while other DA projection regions are less affected. The locomotor activity in lesioned rats is dependent on maintained presynaptic dopamine function. Dopamine synthesis in remaining terminals and reduced dopamine reuptake may act together in counterbalancing the lesion, though the response to pharmacological challenge is diminished. An increase in postsynaptic DA mediated behavior is seen after lesioning. D1 and D2 receptor binding appear to be unaltered in striatal and limbic regions, whereas D1 receptor and Gs protein stimulated adenylate cyclase activity is increased in striatum. The postsynaptic super sensitivity may therefore be due to alterations remote from DA recognition sites. A collateral sprouting of striatal serotonin fibers occurs after the lesion, indicating a competitive interaction in the development of striatal dopamine and serotonin systems. Treatment with 5-HT2 receptor antagonists reduces the hyperactivity seen in lesioned rats, while 5-HT1A receptor mediated behaviors do not differ in lesioned compared to control rats. d -Amphetamine administration leads to a selective decrease in striatal serotonin metabolite levels in the lesioned rats. The levels of substance P, neurotensin, cholecystokininin are reduced in the basal ganglia following lesioning, while no changes in striatal synaptosomal D-aspartate or choline uptake are seen. Thus, a number of pre-and postsynaptic alterations occur in the DA system as well as in other neuronal systems after neonatal 6-hydroxydopamine lesions of mesencephalic dopamine neurons. These alterations appear to act in conjunction to reduce the consequences of early DA lesions, but they could also be involved in the behavioral changes seen after such lesions.