Chronic continuous and intermittent l-3,4-dihydroxyphenylalanine treatments differentially affect basal ganglia function in 6-hydroxydopamine lesioned rats—an autoradiographic study using [ 3H]flunitrazepam

Abstract

The effects of chronic ‘continuous’ and ‘intermittent’ l-3,4-dihydroxyphenylalanine treatments on GABA receptor function in the basal ganglia of rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle was investigated, by autoradiography with [ 3H]flunitrazepam. The 6-hydroxy-dopamine lesion itself, increased [ 3H]flunitrazepam binding in the substantia nigra pars reticulata (+ 17%, with respect to intact side) and entopeduncular nucleus (+44%), but decreased binding in the globus pallidus of the denervated hemisphere (−20%). ‘Intermittent’ l-3,4-dihydroxyphenylalanine treatment reduced the [ 3H]flunitrazepam binding changes observed in the substantia nigra pars reticulata (−13%) and entopeduncular nucleus (−4%), whereas ‘continuous’ infusion of the same daily dose of l-3,4-dihy-droxyphenylalanine had less effect (+14%, substantia nigra pars reticulata; +26%, entopeduncular nucleus). In contrast, the [ 3H]flunitrazepam binding decrease in the globus pallidus of the 6-hydroxydopamine lesioned animals was unaffected by either regime of chronic l-3,4-dihydroxyphenylalanine treatment. The changes in GABA receptor function implied by these results provide further insight into the pathophysiological effects of l-3,4-dihydroxyphenylalanine treatment on basal ganglia function, following dopamine denervation. In accordance with existing electrophysiological and biochemical evidence on this subject, the main implications of these results include reduced GABA sensitivity of neurons in the entopeduncular nucleus and substantia nigra pars reticulata, following chronic ‘intermittent’, but not chronic ‘continuous’ l-3,4-dihydroxyphenylalanine treatment; this may be due to a reversal of the 6-hydroxydopamine induced decrease in the GABA-mediated neurotransmission in the striatoentopeduncular and striatonigral pathways. In contrast, the regulation of GABA receptors in the globus pallidus does not appear to be subject to modulation by chronic l-3,4-dihydroxyphenylalanine administration, suggesting that dopamine replacement in this manner does not modify the 6-hydroxydopamine induced increase in GABA-mediated neurotransmission in the stratopallidal pathway.