Regenerative critical periods for locus coeruleus in postnatal rat pups following intracisternal 6-hydroxydopamine: a model of noradrenergic development.

Rat pups were injected intracisternally with 20, 40 or 80 microgram of 6-hydroxydopamine (6-OHDA) at various ages over the first 12 postnatal days in order to determine the critical period of the noradrenergic regenerative-sprouting response in the cerebellum. Twenty-four hours after the treatment NE fibers in the cerebellum had become extensively degenerated. NE levels were reduced by greater than 90-95% and histofluorescence microscopy revealed an absence of innervation except for lesioned axon stumps in the basal white matter and peduncles. The 80 microgram dose produced considerable cellular degeneration in the locus coeruleus and no regenerative growth was seen to follow this treatment. Following the two lower doses, however, regenerative growth did occur. This was maximal in those rats treated closest to birth and declined progressively to become insignificant in rats which were treated on postnatal days 5-12, depending upon the cerebellar subregion. This decline in regenerative potential paralleled the time course for development of NE levels in control cerebella. For this reason the mechanism(s) controlling noradrenergic developmental and regenerative growth in the cerebellum appear to be similar. Such regenerative growth may thus be a useful model for the study of developmental growth of locus coeruleus axons. Contrary to the cerebellar projection, regenerative growth of the forebrain noradrenergic projection was not detected until the rats were between 7 and 12 days old at the time of treatment. This regeneration in the cerebral cortex was preceded by incomplete initial destruction of NE fibers there, in apparent similarity to regenerative growth described to occur in the adult rat forebrain.