Journal of Neuroscience, Vol 15, 6157-6166, Copyright © 1995 by Society for Neuroscience
Activation of dopamine cell firing by repeated L-DOPA administration to dopamine-depleted rats: its potential role in mediating the therapeutic response to L-DOPA treatment
DG Harden and AA Grace
Department of Neuroscience, University of Pittsburgh, Pennsylvania 15260, USA.
The administration of L-dihydroxyphenylalanine (L-DOPA) to patients with
Parkinson's disease is known to produce acute effects that include the
reduction of rigidity as well as delayed therapeutic actions involving the
resumption of complex motor behavior. In order to examine the potential
role of dopamine (DA) cell activity in mediating these responses, the
effects of acute and repeated L-DOPA administration on the
electrophysiological activity of the residual dopamine (DA) neurons were
examined in rats that had received partial 6-hydroxydopamine (6-
OHDA)-induced DA lesions. DA cell activity was assessed along three
dimensions: (1) the relative proportion of DA neurons exhibiting
spontaneous spike firing, (2) their basal firing rate, and (3) their firing
pattern. Following 6-OHDA-induced DA depletion, rats were treated for 1
month with saline or L-DOPA. In addition, rats from each group received
either an acute injection of L-DOPA or saline on the day of recording. In
rats receiving repeated saline treatment, the DA neurons recorded following
acute L-DOPA administration were firing at significantly slower basal
firing rates and exhibited less burst firing when compared to
saline-pretreated rats given acute saline. In contrast, DA cells recorded
from rats that had received repeated L-DOPA administration for 4 weeks
followed by an acute saline injection did not exhibit any significant
differences from DA cells of intact control rats with respect to basal
firing rate or firing pattern; however, there was a substantial increase in
the proportion of DA neurons exhibiting spontaneous spike firing after
correcting for 6-OHDA-induced cell loss. In addition, in rats receiving
repeated L-DOPA treatment, the DA cells recorded following acute
administration of L-DOPA showed significantly less of a reduction in firing
rate when compared to the cells recorded following acute L-DOPA in the
saline treatment group. These results show that: (1) acute L-DOPA
administration appears to exert its actions by DA autoreceptor stimulation,
whereas (2) repeated L-DOPA administration increases the proportion of
spontaneously active DA neurons in partially lesioned rats. As a result,
repeated L-DOPA administration would be expected to cause an increase in
spike- dependent DA release as a consequence of the greater proportion of
DA cells showing spontaneous activity. This may be the major factor
underlying the delayed therapeutic benefits of L-DOPA therapy in the
treatment of Parkinson's disease.
Previous Article | Next Article
