# Individual Differences & Cocaine Effects on Impulsive Choice in Rat

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $531,868

## Abstract

Cocaine dependence is associated with dysfunctional midbrain cortico-limbic-striatal circuits that impact
decision-making processes and lead to the development of compulsive drug-seeking behaviors. Our new and
published data from the prior funding period show that (1) that the reinforcement-learning mechanisms that
predict cocaine-taking behaviors (e.g., positive-outcome updating) differ from those that are disrupted following
cocaine self-administration (e.g., negative-outcome updating), (2) that midbrain D3 BPND is predictive of
cocaine-taking behaviors and related to positive-outcome updating, but cocaine self-administration disrupts
prefrontal cortical (PFC) mGlu5 BPND and is related to negative-outcome updating, and (3) that positive-
outcome updating is controlled by amygdala projections to the PFC whereas negative-outcome updating is
controlled by PFC projections to the nucleus accumbens (NAc). These findings, collectively, indicate that the
biobehavioral mechanisms that mediate vulnerability to cocaine-taking behaviors differ from those that are
disrupted by chronic cocaine exposure and identify midbrain D3 and cortical mGlu5 receptors as critical
mediators of susceptibility to and consequence of cocaine use, respectively. The functional relevance of
midbrain dopamine D3 and cortical mGlu5 BPND on the neural activity associated with addiction-relevant
behaviors, however, is not known. The studies proposed here will investigate the role of D3 and mGlu5 BPND in
circuit-level mechanisms of decision-making and drug-seeking behaviors in rats. We will use positron emission
tomography (PET) and calcium imaging with fiber photometry to determine how D3 and mGlu5 BPND are
associated with circuit-level activity in rats before and after cocaine self-administration. In Aim 1 we will
investigate the relationship between individual differences in midbrain dopamine D3 BPND and dynamic neural
activity in cortico-limbic circuits during decision making and subsequent cocaine self-administration behaviors.
In Aim 2 we will determine how disruptions in mGlu5 glutamatergic signaling and neural activity mediate
addiction-relevant (seeking/taking) behaviors and alter decision-making strategies after short and long periods
of abstinence from cocaine self-administration. Together, our integrative and novel approach – combining
sophisticated behavioral tasks, computational analyses, in vivo recordings of neural activity with calcium fiber
photometry, and PET imaging – will determine the functional impact and neurobiological mechanisms of
decision-making circuits and their role in addiction vulnerability and pathology.

## Key facts

- **NIH application ID:** 10831447
- **Project number:** 5R01DA043443-08
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Jane R Taylor
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $531,868
- **Award type:** 5
- **Project period:** 2016-07-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831447

## Citation

> US National Institutes of Health, RePORTER application 10831447, Individual Differences & Cocaine Effects on Impulsive Choice in Rat (5R01DA043443-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10831447. Licensed CC0.

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