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Social environment determines the hedonice value of nicotine via molecular and cellular networks in the amygdala

Award Number: R01DA063199
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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Social environment determines the hedonice value of nicotine via molecular and cellular networks in the amygdala - Nicotine addiction is a major public health concern, causing over 480,000 deaths annually in the United States. Despite its addictive properties, initial nicotine exposure in nonsmokers is usually aversive. The initiation of smoking is heavily influenced by social factors, particularly during adolescence. We developed a rat model, Socially Acquired Nicotine Intravenous Self-Administration (SANSA), that simulates the initial negative experience of voluntary nicotine exposure in adolescent rats and observed strong social influence in continued nicotine intake despite this learned negative hedonic value. SANSA employs licking as an operant response to trigger the simultaneous delivery of an oral flavor cue and intravenous (i.v.) nicotine. Adolescent rats tested alone, or in the presence of another rat that does not have access to the flavor cue, develop a conditioned flavor aversion (CFA) that inhibits further intake. In contrast, when the companion rat is also consuming the flavor cue, stable nicotine self-administration is established. Remarkably, SANSA facilitates stable i.v. nicotine self-administration even when an inherently aversive flavor cue is used. We hypothesize that social learning alters nicotine's hedonic value by facilitating the extinction of nicotine-conditioned aversion. Specifically, we propose that the Cacna1c gene, which encodes the Cav1.2 protein and is associated with smoking initiation in human GWAS, and the oxytocin receptor (Oxtr) are critical to this effect, mediated by their interactions in central amygdala (CeA) GABAergic neurons. We will test this via three Specific Aims. Aim 1 focuses on the Cacna1c gene. Using heterozygous rats, we will study the role of Cacna1c in SANSA and the extinction of nicotine CFA mediated by social learning. We will identify additional brain regions activated during social learning and use single-nucleus RNA sequencing (snRNA-seq) to identify transcriptomic changes in the CeA. saCas9-mediated genome editing will selectively knock out Cacna1c in the CeA to provide further support for our hypothesis. Aim 2 focuses on oxytocin signaling in the CeA in modulating SANSA. We will use optogenetic manipulation to control oxytocin release and fiber photometry to monitor real-time neural activity during SANSA. Aim 3 examines interactions between oxytocin and Cav1.2 in CeA GABAergic neurons. We will use RNA-scope to visualize oxytocin receptor and Cacna1c in GABAergic neurons and use electrophysiological recordings to investigate changes in neuron activity in response to oxytocin signaling. The multidisciplinary data collected from this study will significantly enhance our understanding of smoking initiation and provide valuable insights into the processes invoked by the social environment to influence the trajectory of SUD.


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 = $642,758 )
2026	2026	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Drug Use and Addiction Research Programs	000	2	4/8/2026	NON-COMPETING CONTINUATION	$642,758
														Subtotal = $642,758

Issue Date FY: 2025 ( Subtotal = $654,500 )
2025	2025	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Drug Use and Addiction Research Programs	000	1	7/3/2025	NEW	$654,500
														Subtotal = $654,500

Grand Total All Awards = $1,297,258

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Social environment determines the hedonice value of nicotine via molecular and cellular networks in the amygdala

Award Number: R01DA063199

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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