L-type calcium channel blockade attenuates the anxiogenic-like and pro-depressive-like effects of cocaine abstinence in female and male rats

Eric J Nunes; Violet Kimble; Anjali M Rajadhyaksha; Nii A Addy

doi:10.1016/j.neuroscience.2025.01.003

L-type calcium channel blockade attenuates the anxiogenic-like and pro-depressive-like effects of cocaine abstinence in female and male rats

Neuroscience. 2025 Jan 4:S0306-4522(25)00005-3. doi: 10.1016/j.neuroscience.2025.01.003. Online ahead of print.

Authors

Eric J Nunes¹, Violet Kimble¹, Anjali M Rajadhyaksha², Nii A Addy³

Affiliations

¹ Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
² Center for Substance Abuse Research and Department of Neural Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
³ Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, USA; Wu Tsai Institute, Yale University, New Haven, CT, USA; Interdepartmental Neuroscience Program, Yale University, New Haven, CT, USA. Electronic address: nii.addy@yale.edu.

PMID: 39761823
DOI: 10.1016/j.neuroscience.2025.01.003

Abstract

Cocaine abstinence and withdrawal are linked to relapse, heightened anxiety, and depressive-like symptoms. While L-type calcium channels (LTCCs) have been associated with cocaine use disorders in humans and drug-seeking behavior in rodent models, their role in mood-related symptoms during cocaine abstinence remains unclear. This study examined whether blocking LTCCs with isradipine could alter anxiety and depressive symptoms induced by cocaine abstinence. Male and female Sprague-Dawley rats self-administered cocaine or saline, followed by 14 days of abstinence without access to cocaine or saline. They were then assessed for anhedonia, anxiety, and depressive-like behaviors using the sucrose preference test (SPT), elevated plus maze (EPM), and forced swim test (FST). Cocaine-abstinent rats showed increased anxiogenic and pro-depressive responses in the EPM and FST, compared to saline-abstinent rats. However, cocaine abstinent rats showed no changes in the SPT. Systemic administration of isradipine (0.4 mg/kg or 1.2 mg/kg, I.P.), reversed the anxiogenic-like behaviors in female cocaine-abstinent rats, whereas only the higher dose of isradipine (1.2 mg/kg, i.p.) was effective in male cocaine-abstinent rats. In the FST, the lower dose (0.4 mg/kg, i.p.) of isradipine reversed the increased immobility time observed in control cocaine-abstinent female and male rats, with no effect of isradipine on its own in saline-abstinent rats. In contrast the 1.2 mg/kg, i.p. decreased immobility time in both cocaine and saline abstinent female and male rat. In summary, isradipine reversed anxiety and depressive effects associated with cocaine abstinence in a dose- and sex-dependent manner.