L-DOPA-induced increase in TH-immunoreactive striatal neurons in parkinsonian mice: Insights into regulation and function

• DOI: 10.1016/j.nbd.2012.07.012
• Publication Date: 2012-07-20T09:31:28Z
• Authors: Isabel Espadas; Sanja Darmopil; Eva Vergaño-Vera; Oskar Ortiz; Idaira Oliva; Carlos Vicario-Ab...; Eduardo D. Martín; Rosario Moratalla
• Keywords: Male; 0301 basic medicine; Tyrosine 3-Monooxygenase; Parkinson's disease; Dopamine; Dopamine Agents; L-DOPA; Olfactory bulb transplants; Neurosciences. Biological psychiatry. Neuropsychiatry; Aromatic-l-amino acid decarboxylase (AADC); Motor Activity; Levodopa; Mice; 03 medical and health sciences; Parkinsonian Disorders; Animals; Cylinder test; Pitx3 deficient aphakia mice; Mice, Knockout; Neurons; 0303 health sciences; Receptors, Dopamine D2; Receptors, Dopamine D1; Immunohistochemistry; Corpus Striatum; 3. Good health; Mice, Inbred C57BL; D1 and D2 dopamine receptors; Dopamine transporter (DAT); 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; Fast scan cyclic voltammetry; RC321-571

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 functional significance. We previously showed an increase in striatal TH-ir neurons after L-DOPA treatment in mice with unilateral 6-OHDA lesions in the striatum. In the present study, we further examined 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 dose-dependent 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, our experiments in aphakia mice, which lack Pitx3 expression in the brain, indicate that the L-DOPA-dependent increase in the number of TH-ir neurons is independent of Pitx3, a transcription factor necessary for the development of mesencephalic dopaminergic neurons. To explore the possible function of L-DOPA-induced TH-ir neurons in the striatum, we examined dopamine overflow and forelimb use in L-DOPA-treated parkinsonian mice. These studies revealed a tight spatio-temporal 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. Our results suggest that the presence of TH-ir neurons in the striatum may underlie the long-duration response to L-DOPA following withdrawal. Promotion of these neurons in the early stages of Parkinson's disease, when dopamine denervation is incomplete, may be beneficial for maintaining motor function.