This proposal will continue our work examining the role of synaptic plasticity in the response of ventral tegmental area (VTA) neurons to drugs of abuse, using electrophysiological and pharmacological tools. Our studies will contribute at two levels. First, the proposed experiments will define the basic synaptic and circuit properties of this brain region, essential for processing rewarding and aversive stimuli under physiological conditions. Second, we will link these synaptic and circuit properties with responses to ^-opioids in vitro and in vivo. We are especially interested in defining alterations in VTA function that may be candidate mechanisms contributing to their addictive qualities. In this application, I will explore the role of inhibitory VTA synapses in responses to ^-opioids. About 20- 30% of VTA neurons are GABAergic, and opioids and ethanol interact almost exclusively with GABAergic neurons and GABA receptor function. GABA agonists or antagonists delivered into the VTA are rewarding and powerfully influence behavioral responses to addictive drugs. Furthermore, repeated exposure of rats to either cocaine or morphine alters synaptic function at GABAB receptor synapses on VTA neurons, and a single exposure to ethanol alters GABAA receptor synaptic transmission onto VTA dopamine neurons. Chronic treatment with opioids alters the way the VTA circuit is activated by rewarding stimuli, and this is correlated with changes in GABAergic receptor function in the VTA. First we will compare synapses on dopamine neurons with those on GABAergic neurons. We will then examine rapid effects of opioids on GABAergic transmission at relevant VTA synapses, and finally, we will treat animals with morphine in vivo and then test GABAergic synaptic transmission in brain slices to see if changes in GABAA synaptic transmission have occurred. We will also define the properties of the novel LTP of GABAergic synaptic transmission we have recently discovered, and test the effects on IPSC LTP of acute or in vivo treatment with ^-opioids. I expect our work to elucidate the cellular mechanisms by which opioid compounds alter the normal function of this brain area essential for normal reward processing.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA011289-13
Application #
7799885
Study Section
Special Emphasis Panel (ZRG1-MDCN-L (02))
Program Officer
Sorensen, Roger
Project Start
1997-07-15
Project End
2012-01-14
Budget Start
2010-04-01
Budget End
2012-01-14
Support Year
13
Fiscal Year
2010
Total Cost
$288,393
Indirect Cost
Name
Brown University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Polter, Abigail M; Barcomb, Kelsey; Chen, Rudy W et al. (2017) Constitutive activation of kappa opioid receptors at ventral tegmental area inhibitory synapses following acute stress. Elife 6:
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McBain, Chris J; Kauer, Julie A (2009) Presynaptic plasticity: targeted control of inhibitory networks. Curr Opin Neurobiol 19:254-62

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