# Addiction liability, poor attentional control, and cholinergic deficiency

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $384,983

## Abstract

Risk factors for developing addiction include structural abnormalities in cortical and subcortical regions and
associated psychological traits. One such trait concerns the propensity for attribution of incentive salience to
drug-associated cues, rendering such cues to be “attractive” and “magnetic” and capable of instigating drug-
seeking behavior. Sign-tracking rats (STs) approach and contact a Pavlovian conditioned stimulus for food while
their counterparts, the goal-trackers (GTs), also learn about predictive nature of such cues but they do not
approach them. STs have been extensively demonstrated to be vulnerable for developing addiction-like
behaviors and thus have been established as a major animal model of addiction vulnerability. Because
impairments in attentional abnormalities are considered an essential component of psychological traits
associated with addiction vulnerability, we demonstrated that STs exhibit relatively poor attentional performance
that is mediated via low levels of cortical cholinergic neuromodulation. These behavioral and neurochemical
characteristics of STs are consistent with the hypothesis that relatively low levels of cholinergic neuromodulation
bias the subject away from goal-directed attention and toward cue-driven (or bottom-up) attention. We also
showed that, in contrast to GTs, the presence of a Pavlovian cocaine cue fails to increase levels of cholinergic
neuromodulation in STs, thereby fostering attention-capture by the cue and cue-directed behavior. The proposed
research will first test the hypothesis that a failure of the neuronal choline transporter (CHT) to mobilize in
response to stimulation of cholinergic neurons is a cellular mechanism accounting for the attenuated capacity
for cholinergic neuromodulation in STs. Second, we will test the hypothesis that by experimentally attenuating
CHT function and inhibiting basal forebrain cholinergic activity, sign-tracking behavior manifests and, in GTs,
attentional control is diminished, and GTs are more likely to approach a classically conditioned cocaine cue.
Third, based on evidence indicating that stimulation of α4β2* nicotinic acetylcholine receptors (nAChRs)
mediates effects of cholinergic neuromodulation on cortical circuitry, we will test the hypothesis that, in STs, such
a treatment fosters goal-tracking, improves attentional control and reduces the degree to which a cocaine cue
controls behavior. Together, this research will demonstrate that cholinergic-attentional deficits are essential
components of addiction vulnerability traits, that a dysregulated CHT is a neuromarker of the trait indexed by
sign-tracking, and that sign-tracking and associated vulnerabilities can be reversed by upregulating cholinergic
neuromodulation of the cortex.

## Key facts

- **NIH application ID:** 10197075
- **Project number:** 5R01DA045063-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** MARTIN F SARTER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $384,983
- **Award type:** 5
- **Project period:** 2018-09-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197075

## Citation

> US National Institutes of Health, RePORTER application 10197075, Addiction liability, poor attentional control, and cholinergic deficiency (5R01DA045063-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10197075. Licensed CC0.

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