# Glutamate receptor plasticity underlying incubation of methamphetamine craving

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $385,971

## Abstract

In abstinent drug users, environmental cues associated with prior drug use are powerful triggers for relapse.
This project focuses on mechanisms that maintain methamphetamine (Meth) craving and vulnerability to
relapse even after prolonged periods of abstinence. In a rat model of persistent vulnerability to relapse, cue-
induced drug craving progressively intensifies (`incubates') during abstinence from self-administration of many
drugs of abuse, including Meth. Despite recent interest in the incubation of Meth craving, studies at the
synaptic level are lacking. Such studies have the potential to identify novel therapeutic targets. Recently, we
found that strengthening of synapses in the core subregion of the nucleus accumbens (NAc), via incorporation
of high conductance Ca2+-permeable AMPARs (CP-AMPARs), underlies incubation of Meth craving after >40
days of abstinence. We also showed that positive allosteric modulators of mGluR1 remove these CP-AMPARs
from NAc synapses and thereby reduce `incubated Meth craving'. These findings parallel our previous results
on the incubation of cocaine craving. Importantly, however, incubation of craving and CP-AMPAR plasticity
occur much more rapidly after discontinuing Meth (1 week) than cocaine (1 month). The narrower time-frame
will facilitate identification of underlying synaptic mechanisms. However, first it is necessary to define
fundamental parameters of the `incubation model' as it pertains to Meth. The main objective of this proposal is
to determine how alterations in ionotropic glutamate receptor transmission in the NAc and its modulation by
group I mGluRs contribute to the development and expression of `incubated Meth craving'. Our central
hypothesis, formulated based on our cocaine studies and our recently published Meth work, is that incubation-
related plasticity in the NAc begins with decreased mGluR1 function, enabling persistent changes in AMPAR
and NMDAR transmission, which then maintain incubation of Meth craving. We propose 4 Aims that combine
behavioral measures, biochemistry, and whole-cell patch-clamp recordings: 1) Define the time course (rising
and falling phases) of incubation of Meth craving and accompanying CP-AMPAR plasticity in female and male
rats. 2) Determine the subunit composition of CP-AMPARs that accumulate in the NAc core during incubation
of Meth craving and test a potential underlying mechanism. 3) Determine the roles of group I mGluRs in the
development and expression of Meth incubation, focusing on mGluR-LTD in the NAc core and on allosteric
modulation of group I mGluRs as a potential therapeutic strategy. 4) Determine if NMDAR transmission in the
NAc core is altered during the incubation of Meth craving, and if mGluR1 stimulation normalizes NMDAR
plasticity. We expect our studies to define fundamental features of the incubation of Meth craving and its
relationship to alterations in AMPAR, NMDAR and group I mGluR transmission in the NAc core. This in turn
will enable n...

## Key facts

- **NIH application ID:** 9830629
- **Project number:** 5R01DA009621-23
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Marina Elizabeth Wolf
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,971
- **Award type:** 5
- **Project period:** 1996-09-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830629

## Citation

> US National Institutes of Health, RePORTER application 9830629, Glutamate receptor plasticity underlying incubation of methamphetamine craving (5R01DA009621-23). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9830629. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*