# Genetic basis and mechanisms underlying binge-level methamphetamine intake

> **NIH VA I01** · PORTLAND VA MEDICAL CENTER · 2020 · —

## Abstract

Methamphetamine (MA) use can alter judgment, increase unsafe behaviors and violence, and cause mood
disturbances. Chronic use is associated with paranoia, as well as visual and auditory hallucinations. A
number of indicators point to increasing availability and abuse of MA in the United States, especially in the
southern and western regions, among both young and older adults. MA is often taken in repeated binge-
level doses, and individuals who become addicted to MA suffer high rates of relapse, even after prolonged
periods of abstinence. MA is a neurotoxin when higher amounts are taken. Risk as a population measure
can be assessed in animal models in the absence of drug exposure through a number of strategies,
including the use of selectively bred animal lines. The Richards laboratory has developed an animal model
of binge-like MA intake to study genetic risk, neurotoxicity, and changes in behavioral effects of MA
associated with this high level of intake. That model, in concert with a genetic model of resistance to MA
intake that was also developed in the Richards lab, was used to identify trace amine-associated receptor 1
(Taar1) as a gene that accounts for >50% of the genetic variance in MA intake. The high risk allele codes
for a non-functional version of the receptor. However, whereas on an isogenic background, Taar1 allele
type accounts for 92% of the phenotypic variance, it accounts for only 68% of the phenotypic variance on a
mixed genetic background. Furthermore, some individuals that are homozygous for the high risk Taar1
allele retain a low MA intake profile. In addition to examining neurotoxicity associated with binge-level MA
exposure and with differential Taar1 genotype, a focus of this research program will be on the identification
of mechanisms, through transcriptome analyses, that protect against binge-level MA intake in individuals
known to possess a high-risk Taar1 genotype; in other words to identify genetic modifiers. In Aim 1,
controlled binge-level MA dosing and voluntary binge-level MA intake will be compared for their neurotoxic
effects in a high MA intake selected mouse line and in mice of the high MA intake line in which the Taar1
allele that promotes high MA intake has been replaced with the protective allele, a genetic knock-in
approach. In Aim 2, the impact of voluntary binge-level MA intake on conditioned-reward and a reliable
physiological response to MA – body temperature change – will be examined. In Aim 3, a new genetic
model will be developed comprised of bidirectionally selected lines derived from individuals that are all
homozygous for the Taar1 MA risk allele, but are bred for high vs. low MA intake. Although listed as Aim 3,
the production of these lines will begin early in the research program so that they are available for use by
year 3. These lines will also be characterized for MA reward, temperature change, tastant preference and
MA clearance rate. Finally, in Aim 4, analyses will be conducted using t...

## Key facts

- **NIH application ID:** 9840824
- **Project number:** 5I01BX002106-06
- **Recipient organization:** PORTLAND VA MEDICAL CENTER
- **Principal Investigator:** TAMARA J. PHILLIPS
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2014-07-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840824

## Citation

> US National Institutes of Health, RePORTER application 9840824, Genetic basis and mechanisms underlying binge-level methamphetamine intake (5I01BX002106-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9840824. Licensed CC0.

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