# Developing novel tools for targeting mGlu2(3) receptors in methamphetamine addiction.

> **NIH NIH R03** · UNIVERSITY OF FLORIDA · 2020 · $76,250

## Abstract

ABSTRACT
Methamphetamine (meth) use disorder poses unique challenges for treatment due to the prevalence of meth-
induced neurocognitive deficits. These deficits contribute to persistent relapse vulnerability and complicate
recovery for meth users. Here we utilize a rodent model of extended access to self-administered (SA) meth that
captures many symptoms observed in meth users, such as escalation of meth intake, higher propensity to
relapse, cognitive inflexibility and deficits in episodic-like memory. Thus, this model is highly suitable for
investigation of neurobiology underlying persistent meth-induced deficits and for the screening of potential novel
therapeutics. Using this model, we have reported that SA meth reduces cell surface (but not total) expression of
metabotropic glutamate receptors (mGlu) 2/3 in the prefrontal cortex (PFC) that persist for up to 30 days of
abstinence. This finding is highly relevant for meth use disorder as: a) normal function of mGlu2/3 in the PFC is
necessary for optimal cognitive performance, b) increased neuronal activity and enhanced glutamate release in
the PFC observed during meth-seeking could be attributed to reduced control of mGlu2/3 over glutamatergic
neurotransmission, and c) systemic and intra-PFC activation of mGlu2/3 consistently reduces drug-seeking.
However, these studies did not molecularly or pharmacologically separate mGlu2 from 3, and significant
differences in signaling and behavioral output occur when each receptor alone is targeted. Furthermore, no
pharmacological tools exists that would reverse the loss of mGlu2 (or 3) receptor function. The present proposal
is significant because it will be the first to evaluate the surface expression of mGlu2 vs. 3 separately after meth
SA, or otherwise. It will also be the first to consider sex-differences as a factor in such expression. This proposal’s
innovation stems from the development of novel tools (interference peptides) to increase mGlu2(3) surface
availability/function after their in vivo administration. Finally, we aim to develop a highly-translational intranasal
route of administration of such peptides. We hypothesize that this approach will allow for selective restoration of
mGlu2 and/or 3 surface expression and function in subjects with a history of chronic meth exposure. We will test
this hypothesis in the following specific aims: Aim 1- Evaluate sex-differences in surface availability and function
of mGlu2 and mGlu3 in the PFC, and Aim 2- Develop and optimize the in vivo delivery of interference peptides
that reverse post-meth changes in mGlu2 (or 3) surface expression and function in the PFC. To achieve these
ambitious aims, we propose to develop innovative tools – receptor-specific interference peptides. Evidence-
based prediction is that these peptides will normalize the surface expression/function of mGlu2(3) without the
potential side-effects produced by traditional receptor ligands. In summary, the proposed experiments will
evalu...

## Key facts

- **NIH application ID:** 9969341
- **Project number:** 5R03DA049212-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Marek Schwendt
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $76,250
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9969341

## Citation

> US National Institutes of Health, RePORTER application 9969341, Developing novel tools for targeting mGlu2(3) receptors in methamphetamine addiction. (5R03DA049212-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9969341. Licensed CC0.

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