Ventral Tegmental Area GABA Neurons: Plasticity & Opiate Receptors at InhibitoryInputs - Project Summary: 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 the impact of morphine on a novel form of synaptic plasticity of inhibitory inputs as well as excitatory 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, but also cause synaptic modifications on VTA cells, leading to the diseased state of addiction. While known that illicit drugs cause modifications to 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 investigate. 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 basis for examining the effect of other drugs of abuse on GABA plasticity. The long- term goal is to understand normal physiology and morphine-induced modification of inputs to VTA GABA cells. We hope examining opiate-induced VTA neuroadaptations provides a more comprehensive solution in our efforts to reverse addiction. We hypothesize that unique VTA GABA cells that express distinct forms of plasticity that will correlate differentially to VTA GABA neurons that are either projecting or interneurons. We further hypothesize that excitatory and inhibitory forms of GABA cell plasticity will be maladaptively altered by chronic, but not acute, morphine exposure. We also will examine the potential impact of VTA GABA cell plasticity based on the cells unique projections and impact on DA cells. Collectively, this data will provide a better framework of GABAergic circuit role in reward, and morphine effect on synaptic modifications. We will examine this hypothesis using single cell electrophysiology, Retrobeads, rabies virus, optogenetics, and single cell PCR, etc. As currently there are no good treatments to address opiate or other forms of drug-dependence, the identification of a novel target for drugs of abuse could lead to potential new avenues of treatment. 1
