# Trans-synaptic control of GPCR signaling in opioid reward

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2024 · $666,569

## Abstract

PROJECT SUMMARY
 Opioids exert their addictive effects by altering signal processing in the reward circuit of the basal ganglia.
This action involves multiple adaptations, including changes in neuronal wiring and synaptic transmission.
Recent evidence suggests that the glutamatergic system plays a critical role in reward. Particularly, group III
metabotropic glutamate receptors (mGluRs) have been recognized for their role in shaping opioid effects
Located at presynaptic terminals of neurons, group III mGluRs control the strength of glutamatergic actions
and synaptic plasticity of the reward circuit. The overall goal of this research is to understand molecular
mechanisms by which opioids alter glutamatergic signaling and wiring of the reward circuit.
 The focus of this proposal is on ELFN1, a recently discovered cell-adhesion molecule which interacts
with group III mGluRs, modulates their function and plays a key role in establishing synaptic connectivity.
ELFN1 is selectively expressed in cholinergic interneurons (CIN) in the reward circuit hub – nucleus
accumbens (NAc) and its ablation in mice prominently influences opioid effects. Based on accumulated
preliminary data, we hypothesize that the trans-synaptic interaction of ELFN1 in CIN with group III mGluRs on
glutamatergic afferents in the NAc plays a critical role in the structural and functional plasticity of synaptic
communication in the reward circuit to shape opioid effects.
 This hypothesis will be tested by pursuing three complementary Specific Aims that seek to (1) elucidate
the physiological role of ELFN1 in specifying synaptic properties of NAc neurons, (2) determine molecular
mechanisms of ELFN1 action and (3) characterize the contribution of ELFN1-mGluR complexes to rewarding
effects of opioids. The strategy proposed to address these Aims will entail a synergistic combination of
behavioral, genetic, cell-biological, and physiological approaches, exploiting a powerful array of reagents,
animal models, and innovative assays to examine role and mechanisms of ELFN1 in the endogenous setting
of a nervous system. Such studies are expected to provide critical insights into the role of synaptic cell
adhesion molecules in configuring neural circuitry and neuromodulatory receptors involved in reward
processing and opioid use disorder.

## Key facts

- **NIH application ID:** 10879814
- **Project number:** 1R01DA056414-01A1
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Kirill A. Martemyanov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $666,569
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879814

## Citation

> US National Institutes of Health, RePORTER application 10879814, Trans-synaptic control of GPCR signaling in opioid reward (1R01DA056414-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10879814. Licensed CC0.

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