# Novel neuromodulation of motivated and addictive behaviors

> **NIH NIH R21** · UNIVERSITY OF FLORIDA · 2020 · $190,625

## Abstract

Project Summary
Substance use disorders are a significant public health issue, costing tens of thousands of lives and hundreds
of billions of dollars annually
. Considerable efforts have been expended to elucidate the neural mechanisms
underpinning the acute and chronic actions of drugs of abuse on the nervous system, with the hope that better
understanding of these mechanisms will lead to novel therapeutics. Much of this research has targeted receptors
on neurons that are localized to cell bodies, axons, or dendrites; however, neurons also contain primary cilia,
which are microtubule-based organelles that project from the cell bodies of all neurons. The importance of cilia
function for human health is highlighted by the number of diseases caused by cilia dysfunction, several of which
are associated with cognitive and motivational deficits. Neuronal cilia express a variety of G protein-coupled
receptors (GPCRs), several of which are rarely expressed outside of cilia. Notably, several of these receptors,
including the receptor for melanin-concentrating hormone (MCHR1) and the orphan GPCR, GPR88, have been
shown to modulate responses to drugs of abuse. Despite what we know about cilia, our understanding of how
cilia regulate neuronal function and behavior is still limited, and, in particular, there has been no prior research
on interactions between neuronal cilia and drugs of abuse. The long-term goal of this research is to determine
how ciliary signaling contributes to integration of neuromodulatory signals that regulate short- and long-term
responses to drugs of abuse. As a first step toward this goal, the objective of our R21 proposal is to determine
the role of primary cilia on dopaminergic and GABAergic neurons in the VTA and nucleus accumbens,
respectively, in regulation of cocaine-induced behavioral plasticity and reward. This will be accomplished through
molecular-genetic approaches to target cilia loss on specific neuronal types, in combination with behavioral
pharmacological approaches. The proposed experiments will allow us to test our central hypothesis that neuronal
cilia within mesolimbic circuitry are critical regulators of cocaine-induced plasticity and reward. We will test this
hypothesis through two Specific Aims. Experiments in Aim 1 will use novel transgenic mouse strains to determine
a) how cilia loss on dopaminergic and/or GABAergic neurons affects locomotion and locomotor sensitization
induced by acute and repeated cocaine, respectively; b) whether locomotor alterations can be rescued by virally-
mediated restoration of cilia in targeted brain regions, and c) how repeated cocaine alters cilia morphology and
MCHR1 and GPR88 expression in mesolimbic brain regions. Experiments in Aim 2 will use similar approaches
to determine whether cilia on dopaminergic and/or GABAergic neurons are necessary and sufficient for the
rewarding effects of cocaine using a conditioned place preference task. The proposed research is innovative, as
ne...

## Key facts

- **NIH application ID:** 9964750
- **Project number:** 5R21DA047623-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Jeremy McIntyre
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $190,625
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964750

## Citation

> US National Institutes of Health, RePORTER application 9964750, Novel neuromodulation of motivated and addictive behaviors (5R21DA047623-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9964750. Licensed CC0.

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