The Role of Glutamate Release from Ventral Tegmental Area Mu-Opioid Receptor Neurons in Fentanyl Exposure

Capes, Dylan

Undergraduate Honors Thesis

The Role of Glutamate Release from Ventral Tegmental Area Mu-Opioid Receptor Neurons in Fentanyl Exposure Public Deposited

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Citeable URL: https://scholar.colorado.edu/concern/undergraduate_honors_theses/rr172001z

Abstract

The opioid crisis is a worldwide issue that has shown how poorly we understand the impacts and functions of opioids. Understanding the neural circuitry and pathways that opioids hijack to produce their effect can lead to better treatment options and ways of addressing this crisis. We sought to better understand these pathways by investigating a new neuronal subset within the VTA whose glutamate signaling is regulated by the activation of mu-opioid receptors. First, we confirmed that we could genetically manipulate our Oprm1::Cre mouse line with Cre-dependent viral vectors. We then evaluated the behavioral effects of neurotransmitter knockdown in MOR-gated glutamate and GABA neurons within the VTA. These behavioral tests were centered around the motivational affects from fentanyl and fentanyl withdrawal in CPP or CPA, as well as the somatic effects in fentanyl locomotor dose-response and naloxone-precipitated withdrawal. We found that knockdown of glutamate signaling in VTA MOR-gated glutamate neurons produces increased fentanyl-conditioned preference in CPP. We also found that knockdown of GABA signaling in VTA MOR-gated GABA neurons produces decreased fentanyl-conditioned preference in CPP and increases somatic activity in both fentanyl locomotor dose-response and withdrawal symptoms. Ultimately, we concluded that the VTA MOR-gated glutamate neurons play a role in opioid-induced reward, but not in the somatic effects of fentanyl or fentanyl withdrawal. We believe that our conclusions contribute to understanding the role of this newly discovered VTA MOR-gated glutamate population.

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