The transmitter dopamine (DA) is critical for motivation, reward, movement, and cognition. Originating in the ventral tegmental area (VTA), the mesolimbic DA pathway projects to the nucleus accumbens (NAc) core and shell where DA transmission contributes to the rewarding effects of food and drugs, and promotes goal- directed behavior and reward-related learning. Operating in parallel with the mesolimbic system, the nigrostriatal DA pathway originates in the substantia nigra pars compacta (SNc) and projects to the caudate- putamen (CPu). This pathway contributes to motivated behavior and movement, and is involved in driving behaviors that have transitioned from goal-directed and intentional to automatic and compulsive. Given the key roles of these pathways, dysfunction of DA transmission plays a key role in neuropsychiatric disorders including addiction to psychostimulant drugs and the motor deficits of Parkinson's disease. Elucidating causal factors in these disorders, and developing corresponding treatments, requires an understanding of factors that govern DA release. It is often assumed that DA signaling is governed solely by DA neuron firing rate and pattern, with homogeneous activity-dependent changes in extracellular DA concentration ([DA]o) throughout the striatum. However, this is not the case: studies using fast-scan cyclic voltammetry (FCV) show that DA release is regulated locally within the striatum, with temporally and spatially discrete [DA]o transients detected in vivo and in ex vivo brain slices. Preliminary data suggest that a novel source of dynamic local DA release regulation is mediated by glutamate and GABA that are co-released from striatal DA axons. This project will determine autoregulatory roles of co-released glutamate and GABA on axonal DA release in NAc (Aim 1) and CPu (Aim 2), and somatodendritic DA release in VTA and SNc (Aim 3), in ex vivo slices from mice that express channelrhodopsin 2 (ChR2) in DA neurons. Companion studies will assess the presence of glutamate and GABA receptor subunits on striatal DA axons using immuno-electron microscopy. Based on preliminary data showing enhanced AMPA receptor-dependent regulation of striatal DA release in ex vivo slices 24 h after a single cocaine injection, each aim will include examination of the effect of acute cocaine exposure on DA release regulation by co-released transmitters. Overall, this project will define the roles of co-released glutamate and GABA in sculpting how changes in DA neuron activity translate into DA release, and how this regulation can be disrupted by cocaine.

Public Health Relevance

The neurotransmitter dopamine is involved in brain processes including motivation and movement; however, factors that regulate dopamine release remain poorly understood. Using new approaches, we will address the novel question of how co-released transmitters, glutamate and GABA, regulate dopamine release in forebrain and midbrain regions, and how this autoregulatory role may be altered by a single exposure to cocaine. Our results will advance the understanding of dopamine regulation in health and disease, and thereby point to new targets that could be harnessed for therapeutic intervention in disorders that include addiction.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Sorensen, Roger
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New York University
Schools of Medicine
New York
United States
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Rice, Margaret E (2017) Monitoring Molecules in Neuroscience Then and Now. ACS Chem Neurosci 8:215-217
Farooq, Mobeen; Kim, Seonil; Patel, Sunny et al. (2017) Lithium increases synaptic GluA2 in hippocampal neurons by elevating the ?-catenin protein. Neuropharmacology 113:426-433
O'Neill, Brian; Patel, Jyoti C; Rice, Margaret E (2017) Characterization of Optically and Electrically Evoked Dopamine Release in Striatal Slices from Digenic Knock-in Mice with DAT-Driven Expression of Channelrhodopsin. ACS Chem Neurosci 8:310-319
Ludwig, Mike; Apps, David; Menzies, John et al. (2016) Dendritic Release of Neurotransmitters. Compr Physiol 7:235-252
Sulzer, David; Cragg, Stephanie J; Rice, Margaret E (2016) Striatal dopamine neurotransmission: regulation of release and uptake. Basal Ganglia 6:123-148
Rice, Margaret E; Patel, Jyoti C (2015) Somatodendritic dopamine release: recent mechanistic insights. Philos Trans R Soc Lond B Biol Sci 370: