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Neurobiological Factors Contributing to Tolerance to the Adverse Consequences of Alcohol

Award Number: R01AA032271
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: 08/04/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2030

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Neurobiological Factors Contributing to Tolerance to the Adverse Consequences of Alcohol - Project Summary The adverse consequences of alcohol ingestion serve as a primary deterrent to excessive alcohol drinking. Individuals vary drastically in their subjective response to the interoceptive properties of alcohol and those individuals least sensitive to the aversive effects are most at risk for developing an alcohol use disorder (AUD). Moreover, tolerance to these aversive effects develops rapidly following repeated alcohol drinking sessions and this tolerance directly facilitates the escalation of alcohol consumption and binge drinking episodes. It is currently unknown which precise neurobiological mechanisms confer differential sensitivity to the adverse effects of alcohol as is how these same mechanisms are altered following development of tolerance. The insular cortex has gained significant interest lately for its involvement in alcohol drinking and the progression of AUD. Insular cortical neural activity is associated with alcohol craving and alcohol drinking that persists despite adverse consequences. Additionally, insular dysfunction and morphological changes are apparent in long-term alcohol drinkers. Recent work in rodents strongly supports that the posterior insular cortex (pIC) conveys the salience of the adverse properties of alcohol administration and that pIC neural activity is reduced following repeated alcohol drinking sessions concomitant with the development of tolerance to these same properties. Furthermore, pIC neural activity is positively correlated with individual sensitivity to the aversive orosensory properties of alcohol and pIC lesions significantly reduce behavioral responsivity to the adverse consequences of alcohol intoxication. This proposal will employ cutting-edge recombinant viral vector strategies coupled with well-validated alcohol drinking behavioral paradigms to demonstrate that pIC neuronal ensembles critically contribute to the development of tolerance to the adverse effects of alcohol ingestion and that dopaminergic innervation of pIC directly facilitates excessive alcohol consumption in part through reducing the salience of the aversive effects of alcohol intoxication. Additionally, comparative single-cell RNA-sequencing will reveal the transcription profile of specific pIC neurons that are responsive to the initial aversive properties of alcohol experienced upon its first presentation. Furthermore, this same approach will also determine how the transcriptome of these same neurons is altered following induction of tolerance to these aversive properties. Completion of these studies will significantly contribute to our understanding of how discrete insular subregions contribute to the responsivity to the aversive properties of alcohol. Elucidation of the specific neuronal phenotypes involved in the development of tolerance to the adverse consequences of alcohol consumption will aid in attempts to identify treatment strategies to restore sensitivity to these aversive effects in long-term alcohol drinkers and thus promote efforts to achieve, and maintain, abstinence.


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 = $2,120,500 )
2026	2026	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Alcohol Research Programs	000	1	8/6/2026	NEW	$2,120,500
														Subtotal = $2,120,500

Grand Total All Awards = $2,120,500

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Neurobiological Factors Contributing to Tolerance to the Adverse Consequences of Alcohol

Award Number: R01AA032271

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: 08/04/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2030

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