# Dorsal striatal phosphodiesterase 10A and compulsive ethanol use

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2021 · $399,375

## Abstract

ABSTRACT
 Alcohol use disorder (AUD) is a chronic, relapsing disorder that afflicts 29% of Americans in their lifetime1,2,
is disabling2 and increases mortality3. New drug targets and neurobiological insight for AUD are needed.
Compulsive drinking putatively involves a transition to dorsal (vs. ventral) striatal control over drinking and a
relative underactivity of indirect pathway MSNs (iMSNs) that enable adaptive behavioral selection in contrast to
overactive direct pathway MSNs (dMSNs) that drive drinking behaviors. Compulsive drinking also involves a
shift to dorsal (caudate-putamen) from ventromedial (nucleus accumbens) striatal control of ethanol-related
behavior. Guided by novel preliminary data, this multidisciplinary project tests the overarching hypothesis that
decreasing dorsal striatal phosphodiesterase 10A (PDE10A) type 2 activity in indirect medium spiny neurons
(MSN) reduces compulsive drinking. In 4 Specific Aims, we seek to fill molecular, circuitry, pharmacological,
behavioral and human genetic gaps in our understanding of the role of PDE10A isoforms in activation of
distinct striatal MSN pathways and compulsive drinking. Aim 1 seeks to identify translatable PDE10A
inhibitors that reduce compulsive-like ethanol self-administration, with consideration of enzyme off-rate,
lipophilic efficiency and neuroactivational effects on distinct MSN circuits. Aim 2 will intersect Adora2a-Cre
rats with expression of a floxed, validiated PDE10A shRNA to knockdown dorsal iMSN PDE10A in order to
determine this the role of caudate-putamen PDE10A in iMSNs in escalated and aversion-resistant self-
administration. Aim 3 seeks to determine the causal role of the striatal-restricted, membrane-associated
PDE10A2 isoform in compulsive-like ethanol intake. Finally, Aim 4 seeks PDE10A gene variants that
associate with problematic alcohol use as well as their functional, expression, and psychiatric genetic
correlates. The collective work of our assembled, multidisciplinary collaborative team will shed light on the
neurobiological and genetic role of PDE10A isoforms in distinct striatal circuits and compulsive drinking
behaviors as well as the potential impact of novel translatable PDE10A inhibitors to treat AUD.

## Key facts

- **NIH application ID:** 10101552
- **Project number:** 1R01AA028879-01
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** ERIC P ZORRILLA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $399,375
- **Award type:** 1
- **Project period:** 2021-01-15 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10101552

## Citation

> US National Institutes of Health, RePORTER application 10101552, Dorsal striatal phosphodiesterase 10A and compulsive ethanol use (1R01AA028879-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10101552. Licensed CC0.

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