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

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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.