Under normal conditions, adaptive behaviors such as eating and sex activate the reward system, and plasticity in the system serves to reinforce and promote these behaviors. Drugs of abuse bypass the normal requirements for stimulation and confer reward directly, altering the properties of the reward system to produce tolerance, physical dependence and drug craving. Drug addiction thus provides a dramatic example of plasticity in the reward pathway. The neurotransmitter dopamine has a crucial role in the reward pathway. Many drugs of abuse increase extracellular dopamine, and repeated intermittent administration can produce larger behavioral responses to subsequent drug exposure, a phenomenon known as behavioral sensitization that has been considered a model for the core features of addiction. Indeed, sensitization to psychostimulants requires the somatodendritic release of dopamine in the ventral tegmental area to induce this form of plasticity, and involves increased dopamine release in the nucleus accumbens in the expression of this plasticity. Together, these observations indicate that dopamine release and its regulation have an important role in the adaptation to drug use. The long-term objective of this proposal is to understand how drugs of abuse alter dopamine release. The strategy is to focus on the membrane trafficking of proteins involved in dopamine release and signal transduction and their regulation. In Project 1, Dr. Sulzer will use amperometry to understand the regulation of dopamine release through a flickering fusion pore, and other biophysical methods to assess the chronic effects of amphetamine on vesicle acidification. He will also embark on a newer line of investigation to study the mechanism and physiological role of structural changes in dopamine release sites. Dr. von Zastrow (Project 2) will examine the mechanisms involved in opioid and dopamine receptor internalization and recycling by real time imaging in primary neuronal culture. Dr. Edwards (Project 3) will investigate the role of regulated exocytosis in the somatodendritic release of dopamine required for behavioral sensitization. In addition, he will explore the relationship between vesicle filling and membrane recycling by studying the functional interaction of VMAT2 with synaptobrevin. In Project 4, Dr. Ryan will characterize the exocytosis and recycling of SVs in dopamine neurons, working with Dr. Sulzer to resolve differences in the nature of release (full fusion versus kiss-and-run), and with Drs. von Zastrow and Edwards on real-time imaging in live neurons, comparing the properties of regulated exocytosis in axon terminals and dendrites. ? ? ?

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Program Projects (P01)
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Special Emphasis Panel (ZDA1-MXS-M (09))
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Pollock, Jonathan D
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Henke, Adam; Kovalyova, Yekaterina; Dunn, Matthew et al. (2018) Toward Serotonin Fluorescent False Neurotransmitters: Development of Fluorescent Dual Serotonin and Vesicular Monoamine Transporter Substrates for Visualizing Serotonin Neurons. ACS Chem Neurosci 9:925-934
Dunn, Matthew; Boltaev, Umed; Beskow, Anne et al. (2018) Identification of Fluorescent Small Molecule Compounds for Synaptic Labeling by Image-Based, High-Content Screening. ACS Chem Neurosci 9:673-683
Borgkvist, Anders; Lieberman, Ori J; Sulzer, David (2018) Synaptic plasticity may underlie l-DOPA induced dyskinesia. Curr Opin Neurobiol 48:71-78
Liang, Samantha I; van Lengerich, Bettina; Eichel, Kelsie et al. (2018) Phosphorylated EGFR Dimers Are Not Sufficient to Activate Ras. Cell Rep 22:2593-2600
Clark, Samuel D; Mikofsky, Rachel; Lawson, Jacqueline et al. (2018) Piezo High Accuracy Surgical Osteal Removal (PHASOR): A Technique for Improved Cranial Window Surgery in Mice. J Vis Exp :
Siljee, Jacqueline E; Wang, Yi; Bernard, Adelaide A et al. (2018) Subcellular localization of MC4R with ADCY3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesity. Nat Genet 50:180-185
Eichel, Kelsie; JulliƩ, Damien; Barsi-Rhyne, Benjamin et al. (2018) Catalytic activation of ?-arrestin by GPCRs. Nature 557:381-386
Dunn, Matthew; Henke, Adam; Clark, Samuel et al. (2018) Designing a norepinephrine optical tracer for imaging individual noradrenergic synapses and their activity in vivo. Nat Commun 9:2838
Fischer, Kathryn D; Houston, Alex C W; Desai, Rajeev I et al. (2018) Behavioral phenotyping and dopamine dynamics in mice with conditional deletion of the glutamate transporter GLT-1 in neurons: resistance to the acute locomotor effects of amphetamine. Psychopharmacology (Berl) 235:1371-1387
Eichel, Kelsie; von Zastrow, Mark (2018) Subcellular Organization of GPCR Signaling. Trends Pharmacol Sci 39:200-208

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