# L-Type Calcium Channel Mechanisms Mediating Comorbid Substance Use and Mood Disorders

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $367,726

## Abstract

Individuals with substance use disorders (SUDs) have a higher prevalence of mood and anxiety disorders, and
those with mood disorders also have a higher prevalence for SUDs. Periods of drug abstinence are also
associated with increased irritability, heightened anxiety, and increased mood disorder symptoms. Further,
repeated exposure to either drugs of abuse or stress is associated with mood-related disorders. Thus, the
comorbidity between substance abuse and mood disorders is an ongoing challenge for the field. There is a
need for both improved understanding of mechanisms mediating this comorbidity and a need for novel and
effective therapeutic targets. Research continues to reveal overlapping mechanisms, notably in brain reward
pathways, mediating both SUDs and mood-related disorders. In humans, L-type calcium channel (LTCC)
genes have been identified as candidate risk genes for cocaine dependence, major depressive disorder, and
heightened anxiety. In rodent models, we have found that activation of L-type calcium channels (LTCCs) in the
ventral tegmental area (VTA) enhances cocaine-related, depression-like, anxiety-like, and anhedonic behavior,
while also inducing social deficits. We have also found that LTCC blockade leads to decreased drug-seeking
behavior via regulation of dopamine signaling in the nucleus accumbens (NAc). However, the field still lacks in
depth understanding of LTCC mechanisms in neuropsychiatric disorders. More specifically, there is very
limited understanding of LTCC mechanisms mediating depression and anxiety-related phenotypes induced by
exposure to drugs of abuse or chronic stress – represent a gap in scientific knowledge. Our preliminary
findings have revealed that LTCC blockade in cocaine abstinent or chronic stress exposed rats induces
anxiolytic-like and antidepressant-like effects. In the current proposal, we will integrate intravenous drug self-
administration and chronic unpredictable stress (CUS) paradigms with behavioral pharmacology and in vivo
electrochemistry (voltammetry) in male and female rats to: 1) Determine whether LTCC blockade produces
anxiolytic-like and antidepressant-like effects and promotes social interaction during cocaine abstinence, via
regulation of DA signaling and, 2) Determine whether LTCC blockade attenuates the anxiogenic and
anhedonic effects, and the social interaction deficits, of CUS. In this proposal, we will identify the underlying
mechanisms by which LTCC blockade may serve as a novel therapeutic intervention to alleviate mood disorder
symptoms associated with repeated exposure to cocaine or stress.

## Key facts

- **NIH application ID:** 10266131
- **Project number:** 5R01DA050454-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Nii A Addy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $367,726
- **Award type:** 5
- **Project period:** 2020-09-30 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10266131

## Citation

> US National Institutes of Health, RePORTER application 10266131, L-Type Calcium Channel Mechanisms Mediating Comorbid Substance Use and Mood Disorders (5R01DA050454-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10266131. Licensed CC0.

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