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Impact of fentanyl consumption on noradrenergic plasticity in the basolateral amygdala

Award Number: K01DA061050
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/01/2025
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Impact of fentanyl consumption on noradrenergic plasticity in the basolateral amygdala - Project Summary Opioid use disorders have an enormous societal impact in the United States and opioid overdose deaths are now the leading cause of accidental death in the United States. The impacts of opioid use disorder have worsened over the past decade due to prevalence of high potency synthetic opioids, like fentanyl, that pose unique problems for clinical treatment. Opioid withdrawal is a key contributor to opioid use disorder because withdrawal acts as a negative reinforcer to drive continued opioid consumption. Opioid withdrawal consists of both somatic and negative affective behaviors, and long-term opioid use is associated with the development of anxiety and stress. Therefore, it is critical to understand how opioids alter circuits and neurotransmitters that regulate addiction-like behaviors and negative affect. The basolateral amygdala (BLA) is a key component of the stress response and encodes aversive memories. The BLA receives noradrenergic innervation from A2-NE neurons located in the nucleus of the solitary tract, and this cell population is activated by opioid withdrawal. Notably, chronic stress disrupts noradrenergic plasticity in the BLA, and altered NE signaling in the BLA contributes to negative affect and disruptions in conditioned fear extinction. Despite these links, this pathway has been relatively underexplored in the context of opioid use disorder. My preliminary data demonstrate that A2-NE neurons are hyperactive and hyperexcitable following morphine withdrawal. I developed a mouse model of chronic oral fentanyl consumption, where mice consume escalating concentrations of fentanyl for 5 weeks in a drinking in the dark (DiD) model. I observed sex differences in withdrawal behaviors following naloxone- precipitated withdrawal. Following fentanyl consumption, BLA principal neurons had reduced excitatory/inhibitory balance, driven primarily by reduced inhibitory inputs, and increased excitability. Finally, I found that conditioned fear extinction is reduced following fentanyl consumption, while fear learning itself is intact. These data inform the central hypothesis of my proposal that will be investigated in 3 aims: 1. Patterns of fentanyl consumption and withdrawal induce changes in brainstem A2-NE neurons to drive increased excitability and tonic activity (Aim 1). 2. Increased excitability of A2-NE neurons drives increased NE release in the BLA, which disrupts BLA NE signaling (Aim 2). Finally, we hypothesize that increased NE neurotransmission and altered BLA NE signaling drives extinction learning deficits following fentanyl consumption (Aim 3).


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $184,706 )
2026	2026	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Drug Use and Addiction Research Programs	000	2	4/2/2026	NON-COMPETING CONTINUATION	$184,706
														Subtotal = $184,706

Issue Date FY: 2025 ( Subtotal = $184,706 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Drug Use and Addiction Research Programs	000	1	4/18/2025	NEW	$184,706
														Subtotal = $184,706

Grand Total All Awards = $369,412

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Impact of fentanyl consumption on noradrenergic plasticity in the basolateral amygdala

Award Number: K01DA061050

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/01/2025

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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