The long-term objective of the proposed research is to understand, at the biochemical level, the basis for the remarkable initial efficacy of L-DOPA as a therapeutic agent for ameliorating the symptoms of Parkinson's disease. Further, we wish to determine the underlying mechanisms that are responsible for the eventual decline in the ability of Parkinsonian patients to tolerate L-DOPA due to unwanted side effects that emerge usually after five to eight years of taking the drug. Despite its shortcomings as a therapeutic agent, L-DOPA remains the most efficacious and widely utilized compound for treating Parkinsonian symptomatology. By better understanding the neurobiology associated with the beneficial as well as the undesirable actions of L-DOPA we will increase our knowledge of this disorder which then ca be applied to the development of improved therapeutic strategies. In addition, such information will contribute to our understanding of both normal and disordered functioning of the basal ganglia. The proposed studies will utilize the 6-OHDA treated rat as an animal model of Parkinson's disease. In vivo microdialysis, a method enabling repeated measurements of extracellular neurotransmitter levels to be conducted in awake animals, will be employed to determine the characteristics of striatal dopamine release after administration of L-DOPA to animals modelling the early stage of Parkinson's disease when the loss of nigrostriatal dopamine is only partial. These data will be compared to previous results obtained in animals modelling the final stage of the disorder when nigrostriatal dopamine degeneration is nearly complete. We also propose to explore the possibility that pharmacological manipulation of the striatal serotonin innervation, which is relatively spared in the late stage of Parkinsonism, may provide means to supply a physiological source of dopamine formed from L-DOPA in severely dopamine-depleted animals and that such an approach may ultimately prove useful for circumventing the problem of emergent, unwanted side effects. Finally, we propose to evaluate the contribution of dopamine acting at basal ganglia sites outside of the primary target region in striatum to the biochemical effects of L-DOPA that occur in this animal model in order to understand the actions of this compound in the context of the basal ganglia circuitry as a whole.

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Jaumotte, Juliann D; Wyrostek, Stephanie L; Zigmond, Michael J (2016) Protection of cultured dopamine neurons from MPP(+) requires a combination of neurotrophic factors. Eur J Neurosci 44:1691-9
Ayadi, Amina El; Zigmond, Michael J; Smith, Amanda D (2016) IGF-1 protects dopamine neurons against oxidative stress: association with changes in phosphokinases. Exp Brain Res 234:1863-1873
Napier, T Celeste; Corvol, Jean-Christophe; Grace, Anthony A et al. (2015) Linking neuroscience with modern concepts of impulse control disorders in Parkinson's disease. Mov Disord 30:141-9
Zigmond, Michael J; Smeyne, Richard J (2014) Exercise: is it a neuroprotective and if so, how does it work? Parkinsonism Relat Disord 20 Suppl 1:S123-7
Jaumotte, Juliann D; Zigmond, Michael J (2014) Comparison of GDF5 and GDNF as neuroprotective factors for postnatal dopamine neurons in ventral mesencephalic cultures. J Neurosci Res 92:1425-33
Ahrens, Allison M; Nobile, Cameron W; Page, Lindsay E et al. (2013) Individual differences in the conditioned and unconditioned rat 50-kHz ultrasonic vocalizations elicited by repeated amphetamine exposure. Psychopharmacology (Berl) 229:687-700
Zigmond, Michael J; Cameron, Judy L; Hoffer, Barry J et al. (2012) Neurorestoration by physical exercise: moving forward. Parkinsonism Relat Disord 18 Suppl 1:S147-50
Cohen, Ann D; Zigmond, Michael J; Smith, Amanda D (2011) Effects of intrastriatal GDNF on the response of dopamine neurons to 6-hydroxydopamine: time course of protection and neurorestoration. Brain Res 1370:80-8
El Ayadi, Amina; Zigmond, Michael J (2011) Low concentrations of methamphetamine can protect dopaminergic cells against a larger oxidative stress injury: mechanistic study. PLoS One 6:e24722
Allen, Erika; Carlson, Kirsten M; Zigmond, Michael J et al. (2011) L-DOPA reverses motor deficits associated with normal aging in mice. Neurosci Lett 489:1-4

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