Drugs of abuse bypass the normal mechanisms that regulate release of dopamine, producing longterm changes in the neural systems that govern reward. Association with dopamine release enables environmental cues to activate the reward pathway, thus promoting either adaptive behavior or drug addiction. However, we still understand little about the physiological mechanisms that regulate dopamine release, the changes in release that underlie both normal, adaptive behavior and addiction, or the mechanisms by which dopamine controls the reward pathway. Dopamine differs from other classical transmitters in several respects. First, dopamine activates G protein-coupled receptors through volume transmission, making it difficult to understand how dopamine can convey a signal with the temporal resolution required to associate transient environmental cues with reward. Interestingly, recent work has shown that dopamine neurons also release glutamate, but the physiological role of glutamate co-release remains unclear. Second, dopamine undergoes release from dendrites as well as presynaptic boutons, and dendritic dopamine release has been considered to play a particularly important role in plasticity of the reward system. Dendritically released dopamine activates autoreceptors on dopamine neurons, and through Dl receptors, appears to influence synaptic inputs onto midbrain dopamine neurons and to control outflow from the basal ganglia through the substantia nigra pars reticulata (SNr). However, the mechanisms responsible for dendritic dopamine release and the physiological role of Dl receptor activation in the midbrain remain unclear. This program will thus address multiple presynaptic mechanisms highly relevant to the release and action of dopamine in the reward pathway: 1) The mechanism of dendritic dopamine release (Projects 1 and 3);2) The mechanism and physiological role of glutamate co-release by dopamine neurons (Project 3);3) Trafficking and regulation

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Program Projects (P01)
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Special Emphasis Panel (ZRG1-MDCN-F (50))
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Sorensen, Roger
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Mosharov, Eugene V; Borgkvist, Anders; Sulzer, David (2015) Presynaptic effects of levodopa and their possible role in dyskinesia. Mov Disord 30:45-53
Choy, Regina Wai-Yan; Park, Minjong; Temkin, Paul et al. (2014) Retromer mediates a discrete route of local membrane delivery to dendrites. Neuron 82:55-62
Tang, Guomei; Gudsnuk, Kathryn; Kuo, Sheng-Han et al. (2014) Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 83:1131-43
Tatti, Roberta; Bhaukaurally, Khaleel; Gschwend, Olivier et al. (2014) A population of glomerular glutamatergic neurons controls sensory information transfer in the mouse olfactory bulb. Nat Commun 5:3791
Cebrián, Carolina; Zucca, Fabio A; Mauri, Pierluigi et al. (2014) MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration. Nat Commun 5:3633
Federici, Mauro; Latagliata, Emanuele Claudio; Ledonne, Ada et al. (2014) Paradoxical abatement of striatal dopaminergic transmission by cocaine and methylphenidate. J Biol Chem 289:264-74
Irannejad, Roshanak; Kotowski, Sarah J; von Zastrow, Mark (2014) Investigating signaling consequences of GPCR trafficking in the endocytic pathway. Methods Enzymol 535:403-18
Tsvetanova, Nikoleta G; von Zastrow, Mark (2014) Spatial encoding of cyclic AMP signaling specificity by GPCR endocytosis. Nat Chem Biol 10:1061-5
Di Fiore, Pier Paolo; von Zastrow, Mark (2014) Endocytosis, signaling, and beyond. Cold Spring Harb Perspect Biol 6:
Karpowicz Jr, Richard J; Dunn, Matthew; Sulzer, David et al. (2013) APP+, a fluorescent analogue of the neurotoxin MPP+, is a marker of catecholamine neurons in brain tissue, but not a fluorescent false neurotransmitter. ACS Chem Neurosci 4:858-69

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