Influence of rostromedial tegmental nucleus GABA neurons in opioid use disorder

About This Grant

Background and Innovation: Despite their dangers, the number of opioid prescriptions written for veterans has increased sharply since 2000, and veterans are more prone than the general population to both suicide and the development of use disorders following opioid treatment. One of the main opioid-sensitive areas in the brain is the rostromedial tegmental nucleus (RMTg), which contains GABA neurons that act as powerful brakes to dopamine neuron activity in the ventral tegmental area (VTA). However, due to its relatively recent discovery (2009), there have been very few basic electrophysiological studies exploring RMTg function or its role in drug self-administration. With a lack of disease-modifying therapeutics to treat opioid use disorder, we require a deeper understanding of RMTg GABA neurons as they are a key opioid-sensitive cell type. Aging is associated with altered function of reward circuitry in the brain. Our preliminary work in mice has shown that spontaneous GABA tone declines with age in the VTA, and we also observed that aged mice intravenously self-administer dramatically larger doses of opioids than young mice. Thus, we hypothesize that increased opioid self-administration with age is due to reduced RMTg  VTA GABAergic transmission, resulting in increased opioid self-administration and increased reinstatement following opioid withdrawal. We will test that here along with the ability of RMTg stimulation to decrease opioid intake and prevent reinstatement of self-administration following withdrawal. This project will leverage our unique ability to perform intravenous opioid self-administration and patch clamp electrophysiology in aged mice along with the collective expertise of our team to study age-related changes in gene expression. Experiments in Aim 1 will use electrophysiology to determine the basic firing properties, input sensitivity, and response to opioids of identified RMTg neurons, as well as dopamine neuron responses to input across the lifespan. Experiments in Aim 2 will determine how chronic opioid self-administration affects the electrophysiological properties of the RMTg, and also determine molecular phenotypes in single RMTg neurons following opioid self-administration in young and old mice. Finally, Aim 3 will test whether restoring RMTg input to dopamine neurons can decrease opioid self- administration in young and old mice, as well as drug seeking following 14 days of withdrawal. Innovative aspects of the project include an in-depth investigation into the RMTg, a lightly studied but highly opioid- sensitive region of the brain. Also, we have the uncommon ability to perform patch clamp electrophysiology and opioid self-administration in old mice (>20 months), which will provide insights into specific interactions between aging and substance use. Significance and Impact to Veterans Healthcare: Prescription of opioids has increased since 2000, especially in the veteran population. Unfortunately, the increased ease of access to opioids coupled with their strong reinforcing properties has fueled the public health crisis commonly termed “the opioid epidemic”. Contrary to what was once believed, opioid treatment for pain can promote opioid use disorder or substitution with stronger or more potent opioids such as heroin or fentanyl analogues, increasing the risk of addiction, overdose, and suicide. Veterans are more prone than the general population to both suicide and opioid use disorder, underscoring the immediate need for more mechanistic studies into opioid addiction. Our results will address a key gap in our knowledge by elucidating the mechanistic interactions between aging and opioid use while establishing the underlying contribution of a key opioid-sensitive population of neurons in the brain. Path to translation/implementation: In addition to determining if the RMTg can be directly targeted for decreasing opioid use and preventing relapse, exploratory experiments in Aim 2 will identify novel pathways and targets for exploration as potential treatments for opioid use disorder in Veterans and aged populations.