# Genetics of Cocaine and Methamphetamine Sensitivity in Drosophila

> **NIH NIH U01** · CLEMSON UNIVERSITY · 2021 · $488,326

## Abstract

PROJECT SUMMARY
Illegal use of psychostimulants, such as cocaine and methamphetamine, incurs huge socioeconomic costs
worldwide. Despite advances in our understanding of the neural mechanisms that mediate substance abuse
and addiction, little is known about genetic risk factors. Genetic studies in human populations are confounded
by genetic and environmental heterogeneity and uncontrolled variation in drug exposure. Drosophila
melanogaster presents a powerful model system to study the genetic underpinnings of drug susceptibility,
since the genetic background and environment, including exposure to drugs, can be controlled precisely. Many
effects of psychostimulants on people are replicated in flies and are likely mediated through the D.
melanogaster dopamine transporter, which has recently been crystallized and shown to bind cocaine and
metamphetamine. Here, we propose to capitalize on natural genetic and phenotypic variation in an outbred
advanced intercross population derived from a population of 205 inbred wild-derived lines of D. melanogaster
with sequenced and well annotated genomes, the D. melanogaster Genetic Reference Panel (DGRP), to
explore the genetic architectures that underlie variation in voluntary consumption of cocaine and
methamphetamine. We will perform extreme QTL mapping and artificial selection combined with DNA and
RNA sequencing as two complementary genetic mapping strategies to identify naturally occurring variants
affecting consumption of cocaine and methamphetamine. We will use segregating variation in the DGRP as
well as mutations and RNAi constructs in co-isogenic backgrounds to perform functional validation experiments
of the candidate genes and variants identified in each approach. We will focus on increased consumption of
cocaine and methamphetamine, since consumption is genetically variable in the DGRP, we have previously
derived selection lines for food consumption under control conditions, and preliminary data show that some
DGRP lines voluntarily consume larger amounts of cocaine or metamphetamine than a 4% sucrose control
solution, suggesting it may be possible to develop a Drosophila model for complex behaviors related to
addiction. The specific aims of this application are: (1) To identify genetic variants in a DGRP-derived
advanced intercross population associated with increased consumption of cocaine and
methamphetamine using extreme QTL mapping by DNA sequencing of pools of extreme individuals
and randomly selected controls. (2) To create lines enriched for variants associated with increased
consumption of cocaine and methamphetamine by long-term artificial selection. (3) To functionally
validate variants and genes associated with increased consumption of cocaine and methamphetamine
from Specific Aims 1 and 2.
orthologs in humans. R
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esults from the proposed experiments under the U01 mechanism will
will focus on testing evolutionarily conserved candidate genes with
 culminate in a
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## Key facts

- **NIH application ID:** 10164745
- **Project number:** 5U01DA041613-05
- **Recipient organization:** CLEMSON UNIVERSITY
- **Principal Investigator:** Robert R. H Anholt
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $488,326
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10164745

## Citation

> US National Institutes of Health, RePORTER application 10164745, Genetics of Cocaine and Methamphetamine Sensitivity in Drosophila (5U01DA041613-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10164745. Licensed CC0.

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