Release of dopamine from mesocorticolimbic synapses underlies important aspects of drug dependence, working memory, the psychosis associated with schizophrenia, and classical conditioning. This research is intended to elucidate the presynaptic mechanisms utilized by midbrain dopamine neurons and to provide a basis for how these mechanisms contribute to psychostimulant-induced alterations in neuronal function. The most significant presynaptic property, quantal release of neurotransmitter via synaptic vesicle exocytosis, has not previously been observable in catecholamine neurons as in fast- acting synaptic systems, due to lack of rapid postsynaptic currents. Recently, we introduced an approach to directly observe quantal release in central monoamine neurons. We found that amphetamine perturbs physiologically-appropriate dopamine release by reducing the number of molecules released per synaptic vesicle exocytic event (quantal size). Our continuing efforts show both quantal size and frequency is strongly regulated by D2-like dopamine autoreceptors, which would be expected to be maximally stimulated during psychostimulant exposure. The objective of this proposal is to determine basic mechanisms by which dopamine autoreceptors regulate dopamine release over durations of minutes to hours and to place this in a context that may elucidate how psychostimulant modulation of presynaptic function (both quantal release and stimulation- independent mechanisms) underlies effects of psychostimulants, such as amphetamine-mediated sensitization and disturbance of physiological DA input. A recent study by our laboratory has shown that in a dopamine (PC 12) cell line, quantal size is regulated by D2-like dopamine autoreceptor-mediated effects on tyrosine hydroxylase. We now present Preliminary Results suggesting that an analogous response occurs in presynaptic terminals of the midbrain dopaminergic projection neurons. Some alternate mechanisms are also addressed. We explain why regulation of quantal size would be an important plastic parameter, particularly for monoamine and other systems where extrasynaptic overt-ow occurs, and suggest how these non- acute, long-lasting autoreceptor-mediated effects in presynaptic dopamine terminals may provide important steps for the initiation of responses such as psychostimulant dependence and sensitization.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA007418-08
Application #
6378542
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (01))
Program Officer
Frankenheim, Jerry
Project Start
1996-09-30
Project End
2002-06-30
Budget Start
2001-07-15
Budget End
2002-06-30
Support Year
8
Fiscal Year
2001
Total Cost
$252,159
Indirect Cost
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Lieberman, Ori J; McGuirt, Avery F; Tang, Guomei et al. (2018) Roles for neuronal and glial autophagy in synaptic pruning during development. Neurobiol Dis :
Borgkvist, Anders; Lieberman, Ori J; Sulzer, David (2018) Synaptic plasticity may underlie l-DOPA induced dyskinesia. Curr Opin Neurobiol 48:71-78
Aguilar, Jenny I; Dunn, Matthew; Mingote, Susana et al. (2017) Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT. Neuron 95:1074-1088.e7
Covey, Dan P; Mateo, Yolanda; Sulzer, David et al. (2017) Endocannabinoid modulation of dopamine neurotransmission. Neuropharmacology 124:52-61
Zucca, Fabio A; Segura-Aguilar, Juan; Ferrari, Emanuele et al. (2017) Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease. Prog Neurobiol 155:96-119
Avegno, Elizabeth M; Salling, Michael C; Borgkvist, Anders et al. (2016) Voluntary adolescent drinking enhances excitation by low levels of alcohol in a subset of dopaminergic neurons in the ventral tegmental area. Neuropharmacology 110:386-395
Kempadoo, Kimberly A; Mosharov, Eugene V; Choi, Se Joon et al. (2016) Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory. Proc Natl Acad Sci U S A 113:14835-14840
Kharkwal, Geetika; Brami-Cherrier, Karen; Lizardi-Ortiz, José E et al. (2016) Parkinsonism Driven by Antipsychotics Originates from Dopaminergic Control of Striatal Cholinergic Interneurons. Neuron 91:67-78
Pereira, Daniela B; Schmitz, Yvonne; Mészáros, József et al. (2016) Fluorescent false neurotransmitter reveals functionally silent dopamine vesicle clusters in the striatum. Nat Neurosci 19:578-86
Freyberg, Zachary; Sonders, Mark S; Aguilar, Jenny I et al. (2016) Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain. Nat Commun 7:10652

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