# Prefrontal cortex in excessive alcohol drinking: role of sigma receptors

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $371,250

## Abstract

ABSTRACT
 Alcohol dependence is a chronic relapsing disorder characterized by compulsive alcohol use and deficits
in cognitive and executive functions. The emerging picture of alcohol addiction is that of a disease of disrupted
control and compulsion, rather than merely of the pursuit of pleasure. Indeed, alcoholic patients exhibit
deficits in cognitive functions governed by prefronto-cortical regions of the brain; these impairments manifest
as increased risk taking, poor decision making, and loss of inhibitory control and they are thought to promote
further excessive drinking. While evidence shows that chronic alcohol exposure results in loss of behavioral
control, little is known about how neurotransmitter systems in prefronto-cortical regions are adversely
impacted by alcohol and how they contribute to the susceptibility to drink excessively.
 This project, to be conducted at Boston University in the rich neuroscience community of Boston,
concerns Sigma-1 receptor (Sig-1R), a molecular chaperone highly expressed in the central nervous system.
 We have shown that blockade of Sig-1R reduce excessive drinking in animal models of alcoholism, while
they do not reduce responding for ethanol in control rats or the intake of sweet solutions. We have also found
that activation of Sig-1R increases the reinforcing efficacy of alcohol, inducing binge-like drinking. Sig-1Rs are
highly expressed in the prefrontal cortex, a brain area which normally exerts “top-down” inhibitory control
over behavior; importantly chronic intermittent alcohol causes a dramatic up-regulation of Sig-1R protein in
prefrontal regions, suggesting that hyperactivity of this system may have a key role in excessive drinking and in
the neuroplasticity observed in alcohol addiction.
 The central hypothesis of this proposal is that hyperactivity of Sig-1R in prefronto-cortical regions
mediates the chronic alcohol-induced high susceptibility to drink excessively. A secondary hypothesis is
that these neuroadaptations of the Sig-1R system mediate chronic alcohol-induced cognitive deficits and the
long-lasting modifications of prefronto-cortical glutamatergic transmission and dendritic spines.
 Aim 1 will identify changes in Sig-1R levels associated with ethanol-dependence and ethanol drinking,
and will determine whether Sig-1R in prefronto-cortical areas mediates excessive alcohol intake and motivation
to drink. Aim 2 will determine whether Sig-1R mediates chronic alcohol-induced alterations in cognitive
function, synaptic glutamate NMDA receptor expression, and dendritic spines in prefronto-cortical areas.
 If the aims are achieved, our understanding of the neurobiological adaptations driving excessive alcohol
intake would significantly increase and new avenues of investigation towards the pharmacological treatment of
alcohol use disorders would open.

## Key facts

- **NIH application ID:** 9923511
- **Project number:** 5R01AA024439-05
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** VALENTINA SABINO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $371,250
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923511

## Citation

> US National Institutes of Health, RePORTER application 9923511, Prefrontal cortex in excessive alcohol drinking: role of sigma receptors (5R01AA024439-05). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9923511. Licensed CC0.

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