Date of Award

5-15-2023

Document Type

Doctoral Dissertation - Open Access

Degree Name

Doctor of Philosophy

Department

Cell Biology

First Advisor

Christopher S. Leonard

Abstract

Addiction to drugs of abuse is a growing problem in today’s society and current treatments often fail to adequately manage the negative withdrawal symptoms that drive relapse. Therefore, development of more effective therapies is a high priority. The orexin neuropeptide system is a key regulator of reward processes and is therefore an attractive therapeutic target. However, the precise impact of chronic drug exposure on orexin neuron function remains largely unknown. Data from a recent publication found that human post-mortem brains from opiate users have smaller but more numerous orexin immunoreactive neurons. Since decreased neuronal soma area suggests increased excitability, we addressed the hypothesis that orexin neuron intrinsic excitability is increased following chronic morphine exposure.

To test this, we used whole-cell patch clamp recordings from orexin-EGFP neurons in brain slices to assess the intrinsic electrical properties of orexin neurons from mice chronically treated with morphine or saline for two weeks. Paradoxically, we found that orexin neurons are less excitable, specifically H-type orexin neurons while sparing D-type. This decreased excitability was prevented by concurrent treatment with a dual orexin receptor antagonist and was also reversed by four weeks of withdrawal.

Taken together, these observations support a model where D and H-type orexin neurons are differentially engaged and impacted by chronic opioid exposure. Additionally, the observation that a dual orexin receptor antagonist successfully blocks the reduction in intrinsic excitability supports a growing literature that dual orexin receptor antagonists may have therapeutic value in disrupting drug induced brain adaptations that drive addiction.

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