Timing: A critical determinant of the functional consequences of neonatal 6-OHDA lesions.

Abstract

Previous data have indicated that intrastriatal (IS) lesions of the dopamine (DA) system early in development result in a selective effect on D1 receptor expression and sensitivity, which is not seen with adult lesions or lesions made later in development. The purpose of the present study was to test the hypothesis that the timing of the lesion is a critical determinant of the consequences of DA depletion during development. Rats received IS injections of 6-hydroxydopamine (6-OHDA) on day of birth/postnatal day 1 (P0/1) or P7, which resulted in similar decreases in the number of DA uptake sites (> or =70% loss), a measure of DA terminal density. As adults, lesioned rats were challenged with DA receptor agonists to examine the functional sensitivity of D1 and D2 receptors. In adulthood, P0/1-lesioned rats exhibited increases in oral dyskinesias and rearing behavior following treatment with the partial D1 receptor agonists, SKF38393 and SKF77434, whereas rats lesioned on P7 exhibited increases in grooming. P7-lesioned rats also exhibited increases in gnawing, explosive jumping, and self-biting behavior following treatment with the full D1 receptor agonist SKF82958, which were not observed in the other groups. The results support the hypothesis that the timing of DA denervation is of paramount importance for governing the functional consequences of neonatal lesions, as measured by the incidence of DA agonist-induced behaviors in adulthood.