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

> **NIH NIH F31** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2022 · $46,752

## Abstract

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.

## Key facts

- **NIH application ID:** 10388742
- **Project number:** 1F31DA053114-01A1
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Amy Claire Leach
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-01-02 → 2024-01-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10388742

## Citation

> US National Institutes of Health, RePORTER application 10388742, Differential Nicotinic Acetylcholine Receptor Modulation of Striatal Dopamine Release as a Mechanism Underlying Individual Differences in Drug Acquisition Rates (1F31DA053114-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10388742. Licensed CC0.

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