Approximately 2 million people are dependent on or abuse opioids in the USA each year (, and NIDA reports that illicit opiate use is on the rise. Accumulating evidence indicates that alcohol consumption and rewarding events cause the release of endogenous opioids in the brain, therefore utilizing the same mu opioid receptors (MORs) and brain circuits involved in opiate addiction. In spite of the magnitude of this problem, we only partially understand how MOR activation causes reward and leads to addiction. Therefore overall objective of this proposal is to investigate the circuits that contribute to opioid reward. MORs in the ventral tegmental area (VTA) are required for morphine reward (Olmstead and Franklin, 1997b;Zhang et al., 2009). VTA neurons release dopamine in the ventral striatum, and it is commonly thought that dopamine released in the ventral striatum causes opioid reward. Yet, lesions of the ventral striatum do not block morphine reward (Olmstead and Franklin, 1996, 1997a;White et al., 2005). Instead, lesions of the medial prefrontal cortex (mPFC) do block morphine reward (Tzschentke and Schmidt, 1999). Therefore the proposed experiments focus on MOR control of mPFC-projecting VTA neurons. Detailed anatomy of this projection will be studied, in particular to test whether the newly discovered VTA glutamate neurons project to the mPFC. Because morphine reward is dopamine-independent in opiate na?ve animals (Bechara et al., 1992;Nader and van der Kooy, 1997), it is critical to determine the effects of MOR activation on both the non-dopamine and dopamine VTA neurons that project to the mPFC. Cortical-projecting neurons will be retrogradely labeled so that they can be identified during brain slice recordings, and pre- and postsynaptic MOR agonist effects will be measured electrophysiologically in these labeled neurons. Following recordings, the neurotransmitter content of the recorded neurons will be directly identified as dopamine, glutamate, or GABA using immunocytochemistry or in situ hybridization. Since electrical stimulation of the mPFC is rewarding (Corbett et al., 1982;Duvauchelle and Ettenberg, 1991), it is hypothesized that MOR activation will excite mPFC-projecting dopamine and glutamate neurons, and inhibit GABA neurons. By improving our understanding of the circuitry involved in opioid reward, this work will enable more effective therapeutic development for disorders that involve VTA and mPFC signaling, including addiction, alcoholism, impulsivity disorders and attention deficit hyperactivity disorder.

Public Health Relevance

The overall goal of the proposed research is to determine the underlying brain circuitry responsible for opiate addiction. Because brain opiate receptors are also activated following alcohol consumption, food consumption, and other natural rewards, the same circuitry also contributes to other disorders such as alcoholism and overeating. By determining the brain pathways involved in opiate reward and addiction, this work will enable more targeted treatments to be developed for these addiction disorders.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Sorensen, Roger
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Saunders, Benjamin T; Richard, Jocelyn M; Margolis, Elyssa B et al. (2018) Dopamine neurons create Pavlovian conditioned stimuli with circuit-defined motivational properties. Nat Neurosci 21:1072-1083
Margolis, Elyssa B; Fujita, Wakako; Devi, Lakshmi A et al. (2017) Two delta opioid receptor subtypes are functional in single ventral tegmental area neurons, and can interact with the mu opioid receptor. Neuropharmacology 123:420-432
Gomes, Ivone; Bobeck, Erin N; Margolis, Elyssa B et al. (2016) Identification of GPR83 as the receptor for the neuroendocrine peptide PEN. Sci Signal 9:ra43
Margolis, Elyssa B; Hjelmstad, Gregory O; Fujita, Wakako et al. (2014) Direct bidirectional ?-opioid control of midbrain dopamine neurons. J Neurosci 34:14707-16
Berthet, Amandine; Margolis, Elyssa B; Zhang, Jue et al. (2014) Loss of mitochondrial fission depletes axonal mitochondria in midbrain dopamine neurons. J Neurosci 34:14304-17
Volman, Susan F; Lammel, Stephan; Margolis, Elyssa B et al. (2013) New insights into the specificity and plasticity of reward and aversion encoding in the mesolimbic system. J Neurosci 33:17569-76
Margolis, Elyssa B; Toy, Brian; Himmels, Patricia et al. (2012) Identification of rat ventral tegmental area GABAergic neurons. PLoS One 7:e42365
Margolis, Elyssa B; Mitchell, Jennifer M; Hjelmstad, Gregory O et al. (2011) A novel opioid receptor-mediated enhancement of GABAA receptor function induced by stress in ventral tegmental area neurons. J Physiol 589:4229-42