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Differential Nicotinic Acetylcholine Receptor Modulation of Striatal Dopamine Release as a Mechanism Underlying Individual Differences in Drug Acquisition Rates

Award Number: F31DA053114
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Differential Nicotinic Acetylcholine Receptor Modulation of Striatal Dopamine Release as a Mechanism Underlying Individual Differences in Drug Acquisition Rates - Project Summary In 2019, an estimated 20.4 million Americans suffered from a substance use disorder (SUD) - a disease that costs the United States over $740 billion annually. The ability to better identify both behavioral and neurobiological markers of increased risk of developing SUD following initial drug use provides a significant opportunity to help prevent the development of SUD in vulnerable populations. Forming a more coherent understanding of the mechanisms that drive differences in vulnerability will also enable the advancement of more effective treatments for individuals already suffering from SUD. While some behavioral traits, such as sensation seeking, are predictive of increased vulnerability, the neurobiological mechanisms underlying these vulnerability-associated traits remain unclear. Sensation seeking can be modeled in rodents by examining locomotor response to a novel environment. This model has shown that rodents exhibiting higher locomotor response acquire self-administration (SA) of drugs more rapidly and stably compared to low responders. Multiple studies have found correlations between locomotor response to a novel environment and mesolimbic dopamine (DA) signaling, which is integral to processing both natural and drug rewards and reward-associated cues. For example, rats with higher novelty response have increased extracellular DA levels following systemic cocaine injection compared to rats with lower novelty response. Higher novelty response is also associated with higher DA transporter levels and faster DA uptake. However, the mechanisms that may drive these differential DA responses and acquisition rates are not fully understood. One mechanism underlying these individual differences may be differential driving of DA release by acetylcholine (ACh) through nicotinic acetylcholine receptors (nAChRs). Our lab has demonstrated that desensitization or blockade of nAChRs in the nucleus accumbens (NAc) augments phasic DA signals in brain slices of HRs, but not LRs. My central hypothesis is that individual differences in vulnerability to rapidly developing high levels of cocaine intake after first experience are driven, in part, by differential modulation of NAc DA signaling by ACh acting at nAChRs. The proposed research plan will examine the role of differential nAChR activation in vulnerability to drug use through the following aims: (1) Examination of individual differences in DA response to reward-associated cues and the role of nAChRs during cocaine self-administration and (2) Assessment of how selective modulation of mesolimbic DA and ACh affects cocaine acquisition rate in rats with higher versus lower responses to novelty. Importantly, investigating the mechanisms underlying vulnerability-associated traits allows us to better identify behavioral and neurochemical markers of substance abuse risk in humans and to stimulate development of more individualized and effective treatments for 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: 2025 ( Subtotal = -$2,290 )
2025	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	000	2	11/27/2024	NON-COMPETING CONTINUATION	-$2,290
														Subtotal = -$2,290

Issue Date FY: 2023 ( Subtotal = $47,694 )
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	001	2	2/7/2023	NON-COMPETING CONTINUATION	$942
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	000	2	11/22/2022	NON-COMPETING CONTINUATION	$46,752
														Subtotal = $47,694

Issue Date FY: 2022 ( Subtotal = $46,752 )
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	000	1	1/2/2022	NEW	$46,036
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	003	1	5/23/2022	NEW	-$1
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	002	1	4/19/2022	NEW	$717
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	001	1	1/2/2022	NEW	$0
														Subtotal = $46,752

Grand Total All Awards = $92,156

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Differential Nicotinic Acetylcholine Receptor Modulation of Striatal Dopamine Release as a Mechanism Underlying Individual Differences in Drug Acquisition Rates

Award Number: F31DA053114

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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