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Examining the role of novel proenkephalin peptides in influencing alcohol-induced cognitive dysfunction

Award Number: R01AA031452
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Examining the role of novel proenkephalin peptides in influencing alcohol-induced cognitive dysfunction - Project Abstract Current treatments of Alcohol Use Disorder (AUD) have shown moderate success in reducing heavy alcohol drinking but are marred with the problem of treatment adherence. In the clinic, opiate receptor pharmaceutics are often combined with cognitive behavioral therapies to improve long-term abstinence. These findings suggest an important relation between endogenous opioid signaling and cognitive factors in the treatment of AUD; however, lapses in treatment can quickly reinstate alcohol drinking, highlighting a knowledge gap in our understanding of how these mechanisms may influence long-term misuse. In this regard, alcohol consumption stimulates the release of endogenous opioids, including enkephalins that bind to mu-type opioid receptors (MOR) commonly found in limbic areas of the brain. The manipulation of MOR signaling alters the rewarding properties of alcohol, with agonists facilitating reward and consumption, and antagonists blocking these responses. The shared relation between opioidergic responses that underlie motivation and cognition are not well understood but present a focal point for addressing complex pathologies that may underlie alcohol-related sensitivities. In this regard, MORs are found in frontal cortical regions that modulate cognitive function, such as the medial prefrontal cortex (mPFC). Preclinical studies in our laboratory demonstrate that alcohol dependence in rats decreases the phosphorylation of MOR in the mPFC, and increases expression of the neuropeptide precursor, proenkephalin (PENK). This pattern of changes overlaps with clinical observations of MOR desensitization in AUD patients. The findings suggest that dependence may dysregulate opioidergic signaling in the mPFC, although the extent to which such conditions surmise changes in the endogenous ligands is unclear. A better understanding is warranted given that adherence to opiate antagonists diminishes over protracted abstinence and may be undermined by molecular intermediates in the processing of small-opioid peptides. Here, we will explore the central hypothesis that non-canonical PENK signaling in the mPFC plays a pivotal role in dysregulating cognitive function during abstinence. Towards this goal, discovery-based and quantitative mass spectrometry approaches will be combined with in vivo microdialysis to broadly capture PENK-mediated signaling in alcohol-dependent rats undergoing abstinence (Aim 1). We will then explore the functional relevance of non-canonical PENK signaling in relation to hyperexcitable states of withdrawal (Aim 2) and induced-deficits in cognitive flexibility (Aim 3). The results are expected to provide insight into druggable targets that extend beyond conventional opioidergic signaling processes and will establish a framework for mechanisms of cortical excitability that may be influential in AUD pathology and cognitive behavior.


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 = $526,293 )
2026	2026	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	000	3	3/26/2026	NON-COMPETING CONTINUATION	$526,293
														Subtotal = $526,293

Issue Date FY: 2025 ( Subtotal = $508,331 )
2025	2025	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	000	2	5/29/2025	NON-COMPETING CONTINUATION	$508,331
														Subtotal = $508,331

Issue Date FY: 2024 ( Subtotal = $511,059 )
2024	2024	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	000	1	4/26/2024	NEW	$511,059
														Subtotal = $511,059

Grand Total All Awards = $1,545,683

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Examining the role of novel proenkephalin peptides in influencing alcohol-induced cognitive dysfunction

Award Number: R01AA031452

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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