Intraventricular injections of 6-hydroxydopamine in 3-day-old rats resulted in the near-total loss of tyrosine-hydroxylase-immunoreactive processes in the striatum when examined 2-6 months later. This destruction of dopamine (DA) afferents was accompanied by an increase in the density of serotonin (5-HT)-immunoreactive fibers in the striatum. The hyperinnervation was most striking in the rostral striatum, an area containing few 5-HT-immunoreactive fibers in control rats. Retrograde tracing, with either horse-radish peroxidase or rhodamine-labelled microspheres, indicated a significant increase in the number of neurons projecting to the rostral striatum from the dorsal raphe nucleus of lesioned animals. The increase was largely confined to the rostral extent of the dorsal raphe, and overlapped the distribution of cells labelled after injections of HRP into caudal striatum of control and lesioned animals. In sections additionally processed for immunocytochemistry, 80-90% of retrogradely labelled raphe neurons in both groups of animals were found to be 5-HT-immunoreactive. None of changes encountered in infant-lesioned rats were observed 2-4 weeks after 6-HDA was given to adult animals. These findings demonstrate that removal of DA afferents during development leads to an enlargement of the serotoninergic projection from the raphe nucleus to the striatum.
Adult rats were given the neurotoxin 6-hydroxydopamine (6-HDA) by means of cerebrospinal fluid to produce large dopamine-depleting brain lesions. Although the animals behaved normally in their home cages, they became akinetic after such treatments as glucoprivation, tail shock, and exposure to severe cold. The neurological impairments were related both to the extent of dopamine depletion and to the intensity of the stress. Drugs known to enhance dopaminergic function were found to reverse the stress-induced neurological deficits, while dopaminergic antagonists potentiated the debilitating effects of stress. After focal lesions were produced by injecting 6-hydroxydopamine directly into specific brain regions, stress-induced akinesia was found to correlate best with dopamine depletion in the corpus striatum, especially the lateral portion of that structure. These and other findings suggest that the acute emergence of parkinsonian symptoms during stress may reflect extensive damage to the dopaminergic nigrostriatal pathway that had been concealed in a preclinical phase, owing to compensatory neurochemical changes in the dopaminergic neurons that yet remain intact.
Rats given large dopamine-depleting brain lesions as adults exhibit severe impairments in ingestive behavior and sensorimotor function. In contrast to these well-known effects, virtually complete destruction of central dopaminergic neurons produced no such dysfunctions when it occurred in neonates. Indeed, rats continued to suckle and grow, albeit somewhat more slowly, and they could be weaned readily when they were 27 days old. Although most brain-damaged animals did not survive weaning when they were 18 days old, whereas controls exhibited no difficulty, this failure appears to be the consequence of their reduced body weight and related inability to maintain body temperature in a relatively cool environment (22 degrees C). Such premature weaning occurred more successfully when growth was stimulated by rearing brain-damaged pups in small litters or when ambient temperatures were raised to 31 degrees C so as to minimize heat loss. These results demonstrate that the effects of near-total dopamine-depleting brain lesions are considerably less severe when they occur in infants than when they occur in adults, and, consequently, they reveal a capacity for neural plasticity during development that is no longer present at maturity.
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