Synaptic transmission mediated by monoamines is terminated by cocaine-sensitive transporters. The overall hypothesis is that adaptations in monoamine release result from acute and repeated treatments with cocaine.
The aims of this proposal are to identify and characterize synaptic adaptations in the Ventral Tegmental Area (VTA) that result from acute and repeated cocaine treatments.
One aim of this proposal is to completely characterize an inhibitory postsynaptic potential caused by the synaptic release of dopamine in the VTA. The hypothesis is that acute and repeated administration of cocaine will change pre- and postsynaptic elements that control this synaptic response. By recording the effects of synaptically released dopamine on dopamine neurons this study will be able to identify adaptive mechanisms at both pre- and postsynaptic sites.
A second aim i s to identify the mechanism by which intracellular calcium regulates the activity of D2- dopamine receptors. When internal calcium is low, the activity of D2-dopamine receptors is high. The hypothesis is that postsynaptic interactions between calcium and D2 receptors will be sensitive to cocaine given both acutely and with repeated treatments. The significance of the proposed studies is two fold. First, the regulation of the firing of dopamine cells by endogenous dopamine through D2-autoreceptors has been known for decades. The proposed experiments will address cellular aspects of that regulation and the effects of acute and chronic cocaine that were not possible previously. Second, the results of this study on both the release of dopamine and sensitivity of D2-dopamine receptors will be a starting point for the understanding of the adaptive changes in the physiology of the dopamine system following cocaine treatment.
| Gantz, Stephanie C; Ford, Christopher P; Morikawa, Hitoshi et al. (2018) The Evolving Understanding of Dopamine Neurons in the Substantia Nigra and Ventral Tegmental Area. Annu Rev Physiol 80:219-241 |
| Robinson, Brooks G; Condon, Alec F; Radl, Daniela et al. (2017) Cocaine-induced adaptation of dopamine D2S, but not D2L autoreceptors. Elife 6: |
| Vaaga, Christopher E; Yorgason, Jordan T; Williams, John T et al. (2017) Presynaptic gain control by endogenous cotransmission of dopamine and GABA in the olfactory bulb. J Neurophysiol 117:1163-1170 |
| Yorgason, Jordan T; Zeppenfeld, Douglas M; Williams, John T (2017) Cholinergic Interneurons Underlie Spontaneous Dopamine Release in Nucleus Accumbens. J Neurosci 37:2086-2096 |
| Passlick, Stefan; Kramer, Paul F; Richers, Matthew T et al. (2017) Two-color, one-photon uncaging of glutamate and GABA. PLoS One 12:e0187732 |
| Robinson, Brooks G; Bunzow, James R; Grimm, Jonathan B et al. (2017) Desensitized D2 autoreceptors are resistant to trafficking. Sci Rep 7:4379 |
| Kramer, Paul F; Williams, John T (2016) Calcium Release from Stores Inhibits GIRK. Cell Rep 17:3246-3255 |
| Gantz, Stephanie C; Robinson, Brooks G; Buck, David C et al. (2015) Distinct regulation of dopamine D2S and D2L autoreceptor signaling by calcium. Elife 4: |
| Kramer, Paul F; Williams, John T (2015) Cocaine Decreases Metabotropic Glutamate Receptor mGluR1 Currents in Dopamine Neurons by Activating mGluR5. Neuropsychopharmacology 40:2418-24 |
| Gantz, Stephanie C; Levitt, Erica S; Llamosas, Nerea et al. (2015) Depression of Serotonin Synaptic Transmission by the Dopamine Precursor L-DOPA. Cell Rep 12:944-54 |
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