# Mechanisms of mGlu1 regulation of cortical inhibition and cognitive function: Implications in adolescent cocaine exposure

> **NIH NIH K99** · VANDERBILT UNIVERSITY · 2024 · $144,235

## Abstract

PROJECT SUMMARY/ABSTRACT
Evidence suggests that cocaine use, notably during critical neurodevelopmental periods like adolescence, is
associated with significant and persistent impairments in cognitive processes like working memory and cognitive
flexibility. Cognitive symptoms are associated with loss of GABAergic inhibitory transmission in the prefrontal
cortex (PFC). Our preliminary data demonstrates that adolescent cocaine exposure induces persistent deficits
in GABAergic somatostatin-expressing interneurons (SST-INs) in the PFC and cognitive performance in
adulthood. Thus, enhancing cortical inhibition represents a novel therapeutic approach to alleviate cognitive
deficits associated with adolescent cocaine exposure and cocaine use disorder (CUD). This therapeutic goal
may be achieved via activation of the mGlu1 subtype of metabotropic glutamate (mGlu) receptor. Leveraging
highly selective mGlu1 positive allosteric modulators (PAMs), we recently found that mGlu1 positively regulates
cortical inhibition via actions on SST-INs and improves cognitive performance. These findings led us to our
central hypothesis that the ability of mGlu1 PAMs to reverse deficits in cortical inhibition and cognitive impairment
associated with adolescent cocaine exposure is likely driven by actions on mGlu1 receptors located on SST-INs
in the PFC. The present proposal will use cutting-edge transgenic mouse lines and pharmacological tools to
elucidate brain region- and cell type-specific mechanisms underlying mGlu1 regulation of cortical inhibition and
cognitive function and their implications following adolescent cocaine exposure. We will test this hypothesis in
three specific aims.
 Aim 1 (K99): To gain expertise in whole-cell patch-clamp electrophysiology to test the hypothesis that
mGlu1 regulates PFC inhibitory transmission via actions on SST-INs.
Aim 2 (K99): To develop expertise in in vivo fiber photometry to test the hypothesis that mGlu1-mediated
activation of PFC SST-INs facilitates working memory performance.
Aim 3 (R00): To apply whole-cell patch-clamp electrophysiology and in vivo fiber photometry to test the
 hypothesis that mGlu1 modulation can ameliorate adolescent cocaine-induced pathophysiology through
 actions on PFC SST-INs.
Together, the proposed studies will expand our current understanding of the critical role of SST-INs in cognitive
processes impaired by adolescent cocaine use and evaluate the therapeutic potential of mGlu1 PAMs in
mitigating these cocaine-induced deficits. I will gain extensive training in whole-cell patch-clamp
electrophysiology and in vivo cell type-specific Ca2+ imaging during touchscreen-based cognitive testing. Training
in these techniques will allow me to apply my interests in behavioral and receptor pharmacology to unanswered
questions about how drug exposure during critical neurodevelopmental periods manifest in physiological and
behavioral consequences of substance use disorders.

## Key facts

- **NIH application ID:** 10884658
- **Project number:** 1K99DA058712-01A1
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Deborah Joyce Luessen
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $144,235
- **Award type:** 1
- **Project period:** 2024-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10884658

## Citation

> US National Institutes of Health, RePORTER application 10884658, Mechanisms of mGlu1 regulation of cortical inhibition and cognitive function: Implications in adolescent cocaine exposure (1K99DA058712-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10884658. Licensed CC0.

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