# Reduction of psychostimulant craving through positive allosteric modulation of mGlu1

> **NIH NIH U18** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $230,471

## Abstract

A major challenge in treating addiction is that vulnerability to cue-induced craving and relapse persist even after
long periods of abstinence. There is presently no FDA-approved medication to lessen psychostimulant craving.
We study persistent relapse vulnerability using the `incubation of craving' model, in which rats exhibit withdrawal-
dependent intensification (incubation) of cue-induced craving over the first weeks of withdrawal, with high levels
of craving then persisting for months. Incubation of craving also occurs in humans. Previously, we showed that
incubation depends on strengthening of synapses in nucleus accumbens (NAc) core via synaptic incorporation
of Ca2+-permeable AMPARs (CP-AMPARs). We then showed that metabotropic glutamate receptor 1 (mGlu1)
positive allosteric modulators (PAMs) internalize these CP-AMPARs (a form of LTD) and thereby reduce cue-
induced craving for cocaine and methamphetamine. The goal of this proposal is to take the first steps towards
advancing the translation of this basic science discovery. Specifically, we hypothesize that mGlu1 PAMs may be
developed as anti-craving drugs to enable recovering psychostimulant users to maintain abstinence by avoiding
cue-induced relapse. Barriers to this goal include less than optimal pharmacokinetic properties of existing PAMs,
but efforts are underway to develop improved drugs for another indication (schizophrenia). Therefore, this
application will address other barriers, with the goal of making mGlu1 PAMs more attractive to potential partners
and thus accelerate their translation as anti-craving drugs. Aim 1 will use the incubation of craving model to
further validate mGlu1 as a target for psychostimulant (cocaine and methamphetamine) craving reduction by
replicating our effects with an additional mGlu1 PAM, conducting dose-response studies, and studying female
rats. While studies in the incubation model have high translational value because we can study craving after
prolonged abstinence from drug self-administration, they are very time-consuming (6-8 weeks) and labor-
intensive. Aim 2 will develop higher throughput screens for the ability of mGlu1 PAMs to internalize CP-AMPARs.
Work from other groups and our preliminary data indicate that mGlu1-induced CP-AMPAR internalization
depends on mGlu1-induced translation of the “LTD protein” oligophrenin-1 (OPHN1). We propose to develop an
in vitro screen that is precisely focused on this target mechanism, i.e., mammalian cells expressing mGlu1 will
be exposed to mGlu1 PAMs (with glutamate) and OPHN1 expression will be measured. As an alternate strategy,
we will evaluate an in vivo screen that is significantly faster than the incubation model. This is based on extensive
work showing that a single i.p. cocaine injection increases CP-AMPAR levels in excitatory synapses on VTA
dopamine neurons within hours. mGlu1 PAMs internalize CP-AMPARs through the same mechanism in the VTA
and the NAc, so their effects in this screen shoul...

## Key facts

- **NIH application ID:** 10106966
- **Project number:** 1U18DA052488-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Marina Elizabeth Wolf
- **Activity code:** U18 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $230,471
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10106966

## Citation

> US National Institutes of Health, RePORTER application 10106966, Reduction of psychostimulant craving through positive allosteric modulation of mGlu1 (1U18DA052488-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10106966. Licensed CC0.

---

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