engleski

L-DOPA-Induced Increase In TH-Immunoreactive Striatal Neurons In Parkinsonian Mice: Insights Into Regulation And Function

Tyrosine hydroxylase (TH)-immunoreactive (ir) neurons have been found in the striatum after dopamine depletion ; however, little is known about the mechanism underlying their appearance or their function. We previously showed an increase in striatal TH-ir neurons after L-3, 4, - dihydroxyphenylalanine (L-DOPA) treatment. In the present study we used mice with unilateral 6- hydroxydopamine (6-OHDA) lesions of the striatum to study the time-course and persistence of the effects of chronic L-DOPA treatment on the appearance and regulation of TH-ir neurons as well as their possible function. We found that the L- DOPA-induced increase in striatal TH-ir neurons is dosedependent and persists for days after L-DOPA withdrawal, decreasing significantly 10 days after L-DOPA treatment ends. Using hemiparkinsonian D1 receptor knock-out (D1R-/-) and D2 receptor knock-out (D2R-/-) mice, we found that the D1R, but not the D2R, is required for the L-DOPA-induced appearance of TH- ir neurons in the dopamine-depleted striatum. Interestingly, L-DOPA also increases the number of TH-ir neurons in mice lacking Pitx3, a transcription factor necessary for the development of mesencephalic dopaminergic neurons. To explore the possible function of L DOPAinduced TH-ir neurons in the striatum, we examined dopamine overflow and forelimb use in L-DOPA-treated parkinsonian mice. These studies revealed a tight spatiotemporal correlation between the presence of striatal TH-ir neurons, the recovery of electrically stimulated dopamine overflow in the lesioned striatum, and the recovery of contralateral forelimb use with chronic L-DOPA treatment and following withdrawal. These results suggest that promotion of striatal TH-ir neurons in the early stages of Parkinson's disease, when dopamine denervation is incomplete, may be beneficial for maintaining motor function.

Parkinson's disease; L-DOPA; D1 and D2 dopamine receptors; Pitx3 deficient aphakia mice; Fast scan cyclic voltammetry; Dopamine transporter (DAT); Aromatic-l-amino acid decarboxylase (AADC); Cylinder test; Olfactory bulb transplants

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