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

Previous data have indicated that intrastriatal (IS) lesions of the dopamin e (DA) system early in development result in a selective effect on D-1 rece ptor expression and sensitivity, which is not seen with adult lesions or le sions made later in development. The purpose of the present study was to te st the hypothesis that the timing of the lesion is a critical determinant o f the consequences of DA depletion during development. Rats received IS inj ections 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 sit es (greater than or equal to 70% loss), a measure of DA terminal density. A s adults, lesioned rats were challenged with DA receptor agonists to examin e the functional sensitivity of D-1 and D-2 receptors. In adulthood, P0/1-l esioned rats exhibited increases in oral dyskinesias and rearing behavior f ollowing treatment with the partial D-1 receptor agonists, SKF38393 and SKF 77434, whereas rats lesioned on P7 exhibited increases in grooming. P7-lesi oned rats also exhibited increases in gnawing, explosive jumping, and self- biting behavior following treatment with the full D-1 receptor agonist SKF8 2958, 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. (C) 1999 Elsevi er Science Inc. All rights reserved.