Presynaptic plasticity of dopamine release in the cortex and basal ganglia is involved in learning cues that elicit cocaine self-administration and underlie selective attention by filtering non-salient stimuli. The objective of this proposal is to characterize mechanisms that mediate presynaptic plasticity at the level of the dopaminergic synaptic vesicle exocytosis. We recently reported that the fusion pores of small DAergic synaptic vesicles can flicker once or multiple times as fast as 10 kHz, thus regulating the amount of transmitter released from a vesicle. This provides the basis for Aim 1, which asks how flickering of fusion pores is regulated. In chromaffin cells, we discovered that the level of vesicle acidification is not invariant but enhanced by cellular activity, which can increase quantal size. In this proposal, we show evidence for enhanced vesicular acidification that may underlie drug actions (e.g., Ritalin), and a means for behavior to feed back to alter long-term transmission. This provides the basis for Aim 2 explores whether psychostimulants regulate quantal size via rebound of vesicular acidification. Finally, we identified how a variety of presynaptic receptors alter DA transmission at the quantal level (e.g., GDNF, D2, nicotinic, and mGluR activation) and why these factors are important for DA as social synapses. Most of the work has been on acute effects of neurotransmitters. New evidence indicates long- lasting effects of neurotransmitters on DA transmission, particularly on the density/formation of axonal presynaptic varicosities. Accordingly, Aim 3 will examine how neurotransmitters regulate DAergic presynaptic varicosity formation.

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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
Bamford, Nigel S; Wightman, R Mark; Sulzer, David (2018) Dopamine's Effects on Corticostriatal Synapses during Reward-Based Behaviors. Neuron 97:494-510
Ullman, Julie C; Yang, Jing; Sullivan, Michael et al. (2018) A mouse model of autism implicates endosome pH in the regulation of presynaptic calcium entry. Nat Commun 9:330
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

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