Learning impairment in rats after 6-hydroxydopamine-induced depletion of brain catecholamines

Abstract

STEIN¹ suggested, on the basis of the effects of amphetamine and other adrenergic drugs on self-stimulation behaviour, that the reinforcement feedback of the consequence of an action was mediated by a noradrenergic pathway in the region of the medial forebrain bundle. Noradrenergic and dopaminergic pathways in this region of the brain have been mapped by Ungerstedt², and Crow^3,4 has suggested that the gustatory and olfactory input to these pathways might fit them for a role in transmitting environmental feedback. Other evidence implicates the dopaminergic nigro-striatal pathway in memory function as well. Microstimulation in the pars compacta of the substantia nigra has been found to produce a memory impairment not found on stimulation of the surrounding nuclei⁵, lesions in the substantia nigra impair learning^6,7 and pharmacological manipulation of the level of dopamine in the substantia nigra can impair learning and performance of cats in a delayed response task⁸. Crow⁹ has found that locus coeruleus lesions may completely abolish learning in a runway situation. This indicates the involvement of monoaminergic-containing neurones in memory function. 6-Hydroxydopamine produces a depletion of brain noradrenaline and dopamine when injected into the lateral ventricle of the rat brain¹⁰, and also a reduction in the activity of the biosynthetic enzyme tyrosine hydroxylase¹¹ consistent with the morphological finding of acute degeneration of the nerve terminals^12,13. Depletion of the monoaminergic neurones using 6-hydroxydopamine would therefore be predicted to impair learning behaviour, and has indeed been found to produce a transitory decrease in responding on a fixed-ratio schedule for water reward¹⁴. This, however, returned to normal within a few days. Conversely, an increase in responding on a variable interval schedule after 6-hydroxydopamine has been found¹⁵.