Dopamine (DA) neurons in the midbrain ventral tegmental area (VTA) play an important role in the rewarding and reinforcing effects of opioids. Within the VTA, opioids acting at the mu opioid receptor inhibit the release of GABA, which leads to the disinhibition of DA neurons (Johnson and North, 1992a). However, GABA synapses onto VTA DA neurons arise not only from local GABAergic neurons, but also from extrinsic sources, at least some of which are likely to be sensitive to opioids. Two major external sources of inhibition onto VTA neurons arise from the nucleus accumbens (NAc) and the ventral pallidum (VP), both of which have been strongly implicated in opioid reward. These inputs have not been well defined, largely due to the technical challenge of isolating individual connections. Nevertheless, our understanding of the neural circuitry underlying opioid reward requires a thorough investigation of the synaptic properties of these VTA afferents. In this grant, we will make use of recently developed optogenetic tools to independently activate axon terminals arising from either the NAc or the VP in conjunction with whole cell patch-clamp electrophysiology from VTA neurons in midbrain slices. This will allow us to compare and contrast these two inputs and to determine how they are regulated by both acute and chronic exposure to opioids. In addition, by combining this powerful technique with retrograde labeling of VTA neurons from particular projection targets, we will be able to determine the detailed microcircuitry of these afferents within the VTA. The data provided by these studies will provide critical information for the development of circuit based models of limbic system function.

Public Health Relevance

Opioid receptors are clinical targets for the treatment of drug addiction, alcoholism and compulsive eating. These studies will enhance our knowledge of how opioid receptors control the neural circuitry underlying motivation and reinforcement. Understanding precisely how opioid receptors alter addictive behaviors will lead to improved pharmacological treatments for these disorders.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Sorensen, Roger
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Fields, Howard L; Margolis, Elyssa B (2015) Understanding opioid reward. Trends Neurosci 38:217-25
Hjelmstad, Gregory O; Xia, Yanfang; Margolis, Elyssa B et al. (2013) Opioid modulation of ventral pallidal afferents to ventral tegmental area neurons. J Neurosci 33:6454-9
Hnasko, Thomas S; Hjelmstad, Gregory O; Fields, Howard L et al. (2012) Ventral tegmental area glutamate neurons: electrophysiological properties and projections. J Neurosci 32:15076-85