# Mechanistic studies of cAMP effectors in cocaine addiction

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $354,200

## Abstract

Project Summary
 Cocaine addiction is a substantial medical and economic burden in the U.S. and worldwide. There
currently are no FDA-approved medications for treating cocaine addiction. Repeated exposure to drugs of
abuse including cocaine induces the upregulation of cAMP-dependent signaling in the mesolimbic system that
initiates the transition to addiction. cAMP has three direct effectors: protein kinase A (PKA), exchange proteins
activated by cAMP (Epac), and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Much
work has been done to characterize the cAMP-PKA signaling pathway in the regulation of drug reinforcement
and addictive behavior. However, few studies have addressed how the “other” cAMP effectors regulate the
cellular and behavioral effects of drugs of abuse. During our prior NIH funding period, we provided the first
evidence for Epac2-mediated modulation of cocaine-induced excitatory and inhibitory synaptic plasticity in
dopamine neurons of the ventral tegmental area (VTA) and conditioned place preference. Drug self-
administration has a high degree of face and predictive validity for abuse liability and is the gold standard for
studying the reinforcing effects of drugs of abuse. However, whether and how Epac regulates cocaine self-
administration remains unknown. Building on work from our previously funded grant period and our preliminary
studies, the long-term goal of this R01 renewal is to test the hypothesis that Epac and HCN act via distinct but
complementary mechanisms to regulate dopaminergic transmission and cocaine-induced long-term plasticity,
and that these mechanisms contribute to cocaine reinforcement and seeking behavior. Using viral-mediated
knockdown, conditional knockouts, fast-scan cyclic voltammetry (FSCV), electrophysiology, and cocaine self-
administration, we will test this hypothesis via three Specific Aims. In Aims I and II, we will unravel the region-
and cell type-specific mechanisms whereby Epac2 in the VTA and nucleus accumbens contribute to cocaine
reinforcement and seeking behavior, respectively. In Aim III, we will determine how cocaine self-administration-
induced, cAMP-mediated adaptations in HCN2 channels in VTA dopamine neurons contribute to cocaine
reinforcement. These detailed, mechanistic studies are expected to provide first evidence that these under-
studied cAMP effectors in the mesolimbic dopamine system regulate reinforced cocaine self-administration and
drug seeking.

## Key facts

- **NIH application ID:** 9975107
- **Project number:** 5R01DA035217-07
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Qing-song Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,200
- **Award type:** 5
- **Project period:** 2014-04-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975107

## Citation

> US National Institutes of Health, RePORTER application 9975107, Mechanistic studies of cAMP effectors in cocaine addiction (5R01DA035217-07). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9975107. Licensed CC0.

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