Understanding the functions of dopamine (DA) requires the localization of all its major sites of action and hence, the identification of cellular processes that express receptors for DA. This is particularly true when considering that DA can signal neurons via unconventional forms of neurotransmission that are not constrained by synapses. We propose to utilize immunocytochemistry, electron microscopy, and quantitative stereological image analysis to address issues of DA receptor localization in the striatum of rats and non-human primates. We propose the following: (1) To qualify the distinguishing ultrastructural characteristics (dimensions, morphological features, and synaptic associations) of cellular processes immunoreactive for DA D1 and D2 receptors in the rat, in order to thoroughly document normal ultrastructure and to provide baseline information for subsequent species and lesion comparison. We hypothesize that the localization of D2 receptors will suggest a greater degree of presynaptic and non-synaptic actions of DA via this receptor subtype. (2) To determine how the ultrastructural characteristics of cellular processes immunoreactive for DA receptors are distinct in the monkey compared to the rat. We hypothesize that comparable synaptic and non-synaptic actions of DA in the two species will be reflected in similar morphology and synaptic relationships of the cellular processes expressing DA receptors. (3) To utilize a dual labeling immunocytochemical strategy to examine the co-distribution of DA D1 and D2 receptors with glutamate NMDA and AMPA receptors. Based on previous physiological data, we hypothesize that the D1 receptor will preferentially co-localize with the NMDA receptor, while the D2 receptor will be non-selectively distributed with both NMDA and AMPA receptors. (4) To examine rats with extensive unilateral lesions of the nigrostriatal DA pathway in order to determine how the distribution and morphology of D1- or D2 - immunoreactive processes is altered. We hypothesize that changes in the distribution and/or expression of DA receptors will reflect a greater degree of non-synaptic transmission and will be detectable as alterations in receptor-expressing cellular elements and their synaptic relationships. A thorough and unbiased quantitative measurement of DA receptor distribution is essential for statistically meaningful analyses of these issues and interpretation of their implications basic DA function and pathology of the basal ganglia.

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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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