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

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $63,217

## Abstract

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:** 10950036
- **Project number:** 3R01DA050454-04S1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Nii A Addy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $63,217
- **Award type:** 3
- **Project period:** 2024-01-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10950036

## Citation

> US National Institutes of Health, RePORTER application 10950036, L-Type Calcium Channel Mechanisms Mediating Comorbid Substance Use and Mood Disorders (3R01DA050454-04S1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10950036. Licensed CC0.

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