This is a renewal application of a highly successful project that has previously elaborated postsynaptic regulation of opioid and dopamine receptors. The studies proposed in the renewal will examine also the presynaptic compartment, specifically focusing on Dl-type dopamine receptors that regulate the direct pathway GABAergic output from striatum / nucleus accumbens, and to precise evaluation ofthe regulation of synaptic vesicle exocytosis from axons.
The Specific Aims of the proposed studies are:
Specific Aim 1. Determine whether rapid DIR trafficking events are restricted to the somatodendritic surface or occur also in axons of MSNs.
Specific Aim 2. Define the effects of extracellular DA dynamics and electrical activity on Dl R endocytosis in MSNs.
Specific Aim 3. Identify functional consequences of DIR trafficking on pre- and post- synaptic signaling. The proposed experiments will define the basic properties of dopaminergic regulation ofthe direct pathway, which controls natural motivated behavior and is critical for the reinforcing effects of addictive drugs. The studies also directly test, and mechanistically elucidate, presynaptic regulation by Dl receptors. This is a fundamental area of cellular neuroscience that is may reveal new approaches for manipulating addictive drug action or treating addictive disorders.

Public Health Relevance

Dopamine signaling in medium spiny neurons ofthe striatum control motivation to natural stimuli and mediate the reinforcing effects of addictive drugs. The proposed studies determin how this signaling works, and examines specific hypotheses for how it is regualted by natural stimuli relative to drugs. This may idenfify specific features of addictive drug action for therapeutic targeting.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
5P01DA010154-18
Application #
8653544
Study Section
Special Emphasis Panel (ZRG1-MDCN-F)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
18
Fiscal Year
2014
Total Cost
$265,051
Indirect Cost
$97,120
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Uchida, Yasunori; Rutaganira, Florentine U; Jullie, Damien et al. (2016) Endosomal phosphatidylinositol 3-kinase is essential for canonical GPCR signaling. Mol Pharmacol :
Gupta, Vijay; Bhandari, Deepali; Leyme, Anthony et al. (2016) GIV/Girdin activates Gαi and inhibits Gαs via the same motif. Proc Natl Acad Sci U S A 113:E5721-30
Sulzer, David; Cragg, Stephanie J; Rice, Margaret E (2016) Striatal dopamine neurotransmission: regulation of release and uptake. Basal Ganglia 6:123-148
Eichel, K; Jullié, D; von Zastrow, M (2016) β-Arrestin drives MAP kinase signalling from clathrin-coated structures after GPCR dissociation. Nat Cell Biol 18:303-10
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 110:386-95
Tsvetanova, Nikoleta G; Trester-Zedlitz, Michelle; Newton, Billy W et al. (2016) GPCR endocytosis confers uniformity in responses to chemically distinct ligands. Mol Pharmacol :
Tian, Xufan; Irannejad, Roshanak; Bowman, Shanna L et al. (2016) The α-Arrestin ARRDC3 Regulates the Endosomal Residence Time and Intracellular Signaling of the β2-Adrenergic Receptor. J Biol Chem 291:14510-25
Varandas, Katherine C; Irannejad, Roshanak; von Zastrow, Mark (2016) Retromer Endosome Exit Domains Serve Multiple Trafficking Destinations and Regulate Local G Protein Activation by GPCRs. Curr Biol 26:3129-3142
Roseberry, Thomas K; Lee, A Moses; Lalive, Arnaud L et al. (2016) Cell-Type-Specific Control of Brainstem Locomotor Circuits by Basal Ganglia. Cell 164:526-37
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

Showing the most recent 10 out of 103 publications