Approximately 2 million people are dependent on or abuse opioids in the USA each year (www.dhhs.gov), 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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA030529-02
Application #
8209062
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Sorensen, Roger
Project Start
2011-01-01
Project End
2015-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$381,994
Indirect Cost
$156,994
Name
Ernest Gallo Clinic and Research Center
Department
Type
DUNS #
173995366
City
Emeryville
State
CA
Country
United States
Zip Code
94608
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; 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