# Dorsal Striatal Adenosine A1 Receptors in Alcohol-Induced Synaptic and Behavioral Plasticity

> **NIH NIH F32** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $44,093

## Abstract

The marked lack of treatment options for individuals suffering from alcohol use disorders (AUDs) raises a critical
need for alternative approaches to study how alcohol exposure persistently alters neurocircuitry. Adenosine A1
receptors (A1Rs) are intriguing targets for alcohol-induced synaptic and behavioral plasticity. Alterations in these
processes are related to key phenotypes observed in AUDs, such as functional tolerance (i.e. reduced motor
intoxication as a consequence of repeated exposure) which contributes to alcohol-related harms (e.g. driving
under the influence). A1Rs influence alcohol consumption, intoxication, and functional tolerance in preclinical
models, although the mechanisms and neurocircuitry involved are poorly understood. Thus, there is a knowledge
gap regarding A1Rs as significant mediators of plasticity driven by repeated alcohol exposure. The dorsal
striatum (DS), a brain region involved in various aspects of behavioral flexibility with regard to alcohol (e.g.
functional tolerance) is a likely target for alcohol effects on A1R neurobehavioral plasticity. Approximately 95%
of cells in the striatum are GABAergic medium spiny neurons (MSNs) which indirectly (via basal ganglia
structures and thalamic loops) regulate output to a variety of motor cortical areas. The DS is comprised of
functionally heterogeneous medial (DMS) and lateral (DLS) subregions, each receiving distinct excitatory
glutamatergic inputs driving MSN activity, including projections from sensorimotor and prefrontal cortices as well
as a variety of thalamic nuclei. Prior work has shown that alcohol exposure disrupts synaptic long-term
depression (LTD) plasticity mediated by other systems (e.g. endocannabinoids) in the DLS. However,
electrophysiology studies have not consistently differentiated between the DMS and DLS and alcohol effects on
A1R plasticity are unknown. In addition, the role of DS A1Rs in the adaptive process of functional tolerance has
yet to be explored. The central hypothesis is that A1Rs within the DS are mediators of alcohol-induced alterations
in glutamate plasticity and behavioral tolerance and that the functional dissociation of the DMS/DLS is a critical
factor in these effects. Knowledge of the involvement of these A1Rs in critical neurobehavioral adaptations will
move us closer to the long-term goal of understanding how alcohol produces persistent changes in the central
adenosine system that influence behavior. Towards this goal, slice electrophysiology, optogenetics, and
transgenic mouse approaches will be combined to address the synapse-specificity (corticostriatal vs.
thalamostriatal) of alcohol exposure effects on A1R-LTD at MSN synapses in the functionally heterogeneous
subregions of the DS (DMS & DLS). In addition, alcohol functional tolerance will be examined following DMS
and DLS viral-mediated deletion of A1Rs. With these data, we will better understand how alcohol exposure
produces lasting effects on excitatory neurotransmissi...

## Key facts

- **NIH application ID:** 10003919
- **Project number:** 5F32AA026488-03
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Brandon Michael Fritz
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $44,093
- **Award type:** 5
- **Project period:** 2018-09-26 → 2021-04-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003919

## Citation

> US National Institutes of Health, RePORTER application 10003919, Dorsal Striatal Adenosine A1 Receptors in Alcohol-Induced Synaptic and Behavioral Plasticity (5F32AA026488-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10003919. Licensed CC0.

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