Ventral Tegmental Area GABA Neurons: Plasticity & Opiate Receptors at Inhibitory Inputs

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Over 22 million people need treatment for illicit drug/alcohol abuse in the U.S. (SAMHSA survey), costing the government $468 billion per year in related expenses. After alcohol and smoking, opiates are the leading cause for those admitted to substance abuse treatment programs. Currently, there is an opiate crisis throughout the US. Opiate abuse resulted in an exponential increase in synthetic opiate-caused deaths from ~3,000 in 2012 to almost 30,000 in 2017 (NIDA website: Aug. 2018). However, individuals attempting to overcome opiate as well as other addictions often relapse. Therefore, a better understanding of the reward circuit, in addition to a complete understanding of opiate targets in the reward circuit is essential. Here we propose to investigate a novel form of synaptic plasticity of inhibitory inputs onto inhibitory GABA cells in the ventral tegmental area (VTA), the brain's reward center. Within the VTA, dopamine-containing cells are involved in motivation and reward. Reward is an essential component of survival, mediated by increased dopamine release from the VTA. Drugs of abuse dramatically enhance dopamine levels beyond normal rewarding behaviors, and cause synaptic modifications on VTA cells, leading to the diseased state of addiction. While known that illicit drugs cause modifications dopamine cell synapses, neither normal synaptic plasticity of GABA neurons nor how opiates alter GABA neuron activity is completely known. This, despite the fact that GABA neurons are involved in vivo in both the perception and associative learning of reward. Therefore, this role in reward makes VTA GABA cells nearly as important as DA cells to understand. As opiates mediate non-pain related actions in the VTA, our findings will paint a clearer picture of neurocircuit adaptations caused by opiates and provide a base for examining the effect of other drugs of abuse on GABA plasticity. The long-term goal is to understand normal physiology and opiate modification of inputs to VTA GABA cells. We hope by examining more fully opiate-induced neuroadaptations in the VTA, it will provide better, more comprehensive solutions to reverse addiction. We hypothesize that inhibitory inputs to VTA GABA cells undergo novel forms of synaptic plasticity and that opiates will alter these synaptic inputs and thus GABA cell activity. We will examine this hypothesis using single cell electrophysiology, optogenetics, and molecular biology. We anticipate VTA GABA cells will exhibit two forms of plasticity and opiates will alter their activity. We will employ optogenetics to activate specific circuits independently thus determining which circuit correlates to each plasticity type and the location of opiate receptors. As currently there are no good treatments to address opiate or other addictions, the identification of a novel target for drugs of abuse could lead to potential new avenues of treatment.