# Role of dopamine D3 and serotonin 2C receptors in the development of an addiction-like phenotype in rats

> **NIH NIH R36** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $54,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Rates of substance use disorders (SUDs) and deaths by drug overdose in the United States have reached epidemic levels;
yet, the behavioral, pharmacological, and neurobiological determinants of one’s vulnerability to develop a substance use
disorder are not well understood. A variety of behavioral and neurochemical phenotypes are thought to predispose rats
to developing addiction-like phenotypes based on the following criteria: (1) difficulty stopping drug use; (2) high
motivation to take the drug; and, (3) continued drug-taking despite adverse consequences. Though a number of studies
suggest that a subset of rats will develop these addiction-like behaviors following long- or intermittent-access to cocaine
self-administration, it is important to note that this conceptual framework does not incorporate a core feature of SUDs,
high levels of dysregulated drug intake. Indeed, when rats self-administer cocaine under short-access conditions, drug
intake tends to be well-regulated, with little inter-subject variability. Conversely, when rats are allowed to self-administer
3,4-methylenedioxypyrovalerone (MDPV; a synthetic cathinone that selectively inhibits uptake at dopamine and
norepinephrine relative to serotonin transporters) under short-access conditions, ~40% of them (i.e., “high-responders”)
develop unusually high levels of drug intake (i.e., ~3-fold greater than “low-responders”). Early studies also suggest that
“high-responders” exhibit high rates of responding during periods of signaled drug unavailability (e.g., drug-seeking), earn
more infusions under a progressive ratio (e.g., increased motivation), and are less sensitivity to punishment by foot shock
(e.g., continue drug-taking despite adverse consequences).
In addition to recapitulating the addiction-like phenotype often reported with long- or intermittent-access to cocaine,
because MDPV self-administration also reliably establishes high levels of dysregulated drug-taking, a core feature of
addiction, we believe that our model provides a novel and robust approach to study the factors that impact one’s
vulnerability to develop a SUD. For instance, mounting evidence suggests that high levels of drug intake and addiction-like
patterns of drug taking can result in more robust neuroplastic changes in dopamine (e.g., increases in dopamine D3
receptors) and serotonin (e.g., decreases in serotonin2C receptors) systems that are known to play key roles in mediating
the reinforcing effects of drugs. The research project aims to utilize IV self-administration in rats to 1) determine the
impact of short-, long-, and intermittent access to MDPV on the development of addiction-like phenotypes in male and
female rats; and 2) determine whether the relationship between the dopamine D3 and serotonin2C receptors (expression
and function) and the development or severity of addiction-like phenotypes varies as a function of drug (MDPV or
cocaine), access condition (short-, long-, intermi...

## Key facts

- **NIH application ID:** 10057748
- **Project number:** 1R36DA050955-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Michelle Riane Doyle
- **Activity code:** R36 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $54,000
- **Award type:** 1
- **Project period:** 2020-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10057748

## Citation

> US National Institutes of Health, RePORTER application 10057748, Role of dopamine D3 and serotonin 2C receptors in the development of an addiction-like phenotype in rats (1R36DA050955-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10057748. Licensed CC0.

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