# Investigating the role of the Sigma-1 receptors in alcohol addiction and associated cognitive deficits and pain states

> **NIH NIH F31** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $24,936

## Abstract

Abstract
 Alcohol use disorder (AUD) is a highly prevalent chronically relapsing disorder characterized by
compulsion to seek and take alcohol and deficits in cognitive and executive function. These symptoms include
disturbances in impulse-control, cognitive deficits, and inability to control alcohol intake. These behaviors are
mediated through chronic alcohol-induced neuroadaptations in fronto-cortical regions of the brain, such as the
anterior cingulate cortex (ACC) – brain areas key for the “top-down” inhibitory control over behavior. The ACC
is also a hub for neuropathic pain, therefore, a potential key site for alcohol-induced hyperalgesia. Several
gaps exist in our current knowledge of how these fronto-cortico regions of the brain mediate these executive
function deficits as well as alcohol-induced hyperalgesia. One potential mechanism is through the sigma-1
receptor (Sig-1R).
 We have found that exposure to chronic intermittent ethanol (CIE) increases Sig-1R levels in the ACC.
Sig-1R antagonists decrease excessive alcohol drinking and motivation in rats exposed to chronic intermittent
ethanol (CIE), and they have been shown to alleviate neuropathic pain. Whether Sig-1Rs in the ACC play a
role in excessive alcohol drinking, loss of inhibitory control, and allodynic state remains unclear. Here we
hypothesize that hyperactivation of Sig-1R in the ACC is caused by chronic alcohol exposure and plays a key
role in alcohol addiction and in the associated cognitive dysfunctions and allodynia. Sig-1R is a molecular
chaperone that plays a key role in glutamatergic signaling, specifically through modulation of the N-methyl-D-
Aspartate (NMDA) receptor. The NMDA receptor, especially within the ACC, plays a key role in pain sensitivity,
alcohol intake and executive function. Thus, I hypothesize that the increases of Sig-1R levels leads to NMDA
receptor redistribution in the ACC, increasing synaptic levels of NMDA subunit GluN2b, hereby driving the
addiction process forward. To test these hypotheses, we will use a viral vector to knockdown Sig-1R in the
ACC prior to exposing them to CIE. Rats will then be tested for excessive alcohol drinking, impulsive action,
and mechanical allodynia. Furthermore, we will investigate physical interactions between Sig-1R and GluN2b
and the effect of Sig-1R knockdown on subcellular localization of GluN2b. The results of these experiments will
give important insights into the role of Sig-1Rs of the ACC in alcohol addiction, and may lead to the
development of novel pharmacological treatments for AUD.

## Key facts

- **NIH application ID:** 10068327
- **Project number:** 1F31AA028191-01A1
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Sema Quadir
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $24,936
- **Award type:** 1
- **Project period:** 2020-07-21 → 2020-11-13

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10068327

## Citation

> US National Institutes of Health, RePORTER application 10068327, Investigating the role of the Sigma-1 receptors in alcohol addiction and associated cognitive deficits and pain states (1F31AA028191-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10068327. Licensed CC0.

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