# Benzodiazepine treatment induced neuroplasticity

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $391,250

## Abstract

Benzodiazepines (BZs) are therapeutic drugs widely used to treat anxiety, insomnia and seizure disorders and
as additional drug therapy in schizophrenia and depression. BZs bind and potentiate the inhibitory activity of
specific subtypes of GABA type A receptors (GABAARs). Despite the efficacy of BZs, their prolonged use is
severely limited by tolerance, dependence and withdrawal. Very little is mechanistically known about the
neuroadaptations that underlie a BZ tolerant brain state. Chronic BZ treatment results in a decrease in BZ
potentiation of GABA activity at GABAARs, suggesting changes in receptor subunit composition and/or function
at inhibitory synapses. Furthermore, the neuroplasticity occurring during BZ treatment is also dependent on
excitatory glutamatergic N-methyl-D-aspartate receptors (NMDAR), as co-administration of NMDAR
antagonists can prevent BZ tolerance. Using a high throughput quantitative proteomic approach to
investigate BZ sedative tolerance-induced changes in the rodent cortex our data show for the first time
significant upregulation of key excitatory synapse components. Together with our prior work showing that
sustained BZ exposure decreases synaptic levels of BZ sensitive GABAARs, these findings generated the
central hypothesis: Benzodiazepine treatment reduces benzo-sensitive GABAAR subtype signaling
concomitant with enhancing excitatory synapse strength. The proposed research capitalizes on the use of
novel optical methods and quantitative proteomics to address the critical knowledge gap in how prolonged BZ
use induces neuroplasticity in both inhibitory GABAAR and excitatory NMDAR signaling. Two independent and
complementary Aims are proposed to test these mechanistic components of BZ tolerance. The first aim will
use quantitative mass spectrometry, electrophysiology, behavioral and pharmacological methods to define and
functionally assess in vivo BZ treatment induced changes in both inhibitory and excitatory synapses of the
rodent cortex. The second aim will apply high resolution imaging techniques and an innovative optical
biosensor for BZ sensitive GABAAR in vitro and in vivo, combined with genetic, biochemical and
electrophysiological approaches to identify BZ treatment induced GABAAR post translational modifications and
cellular mechanisms leading to rapid BZ uncoupling and the progression to BZ sedative tolerance. These
findings will provide new directions for the development of therapeutic approaches to mitigate or avoid BZ
tolerance, addressing a significant unmet public health need.

## Key facts

- **NIH application ID:** 9857084
- **Project number:** 5R01MH114908-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Tija C. Jacob
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $391,250
- **Award type:** 5
- **Project period:** 2019-02-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857084

## Citation

> US National Institutes of Health, RePORTER application 9857084, Benzodiazepine treatment induced neuroplasticity (5R01MH114908-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9857084. Licensed CC0.

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