Nimodipine improves cortical efficiency during working memory in healthy subjects.

Caroline F Zink, Mellissa Giegerich, Greer E Prettyman, Kayla E Carta, Marcus van Ginkel, Molly P O'Rourke, Eesha Singh, Edward J Fuchs, Craig W Hendrix, Eric Zimmerman, Jennifer Breakey, Mark A Marzinke, Pamela Hummert, Jay J Pillai, Daniel R Weinberger, Kristin L Bigos

Journal: Translational psychiatry 2021;10(1):372

PMID: 33139710

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Abstract

The L-type calcium channel gene, CACNA1C, is a validated risk gene for schizophrenia and the target of calcium channel blockers. Carriers of the risk-associated genotype (rs1006737 A allele) have increased frontal cortical activity during working memory and higher CACNA1C mRNA expression in the prefrontal cortex. The aim of this study was to determine how the brain-penetrant calcium channel blocker, nimodipine, changes brain activity during working memory and other cognitive and emotional processes. We conducted a double-blind randomized cross-over pharmacoMRI study of a single 60 mg dose of oral nimodipine solution and matching placebo in healthy men, prospectively genotyped for rs1006737. With performance unchanged, nimodipine significantly decreased frontal cortical activity by 39.1% and parietal cortical activity by 42.8% during the N-back task (2-back > 0-back contrast; P < 0.05; n = 28). Higher peripheral nimodipine concentrations were correlated with a greater decrease in activation in the frontal cortex. Carriers of the risk-associated allele, A (n = 14), had a greater decrease in frontal cortical activation during working memory compared to non-risk allele carriers. No differences in brain activation were found between nimodipine and placebo for other tasks. Future studies should be conducted to test if the decreased cortical brain activity after nimodipine is associated with improved working memory performance in patients with schizophrenia, particularly those who carry the risk-associated genotype. Furthermore, changes in cortical activity during working memory may be a useful biomarker in future trials of L-type calcium channel blockers.

Address: Baltimore Research and Education Foundation, Baltimore, MD, United States.; Lieber Institute for Brain Development, Baltimore, MD, United States.; Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, United States.; Veterans Administration, San Diego, CA, United States.; Department of Neuroscience, University of Pennsylvania, Philadelphia, PA, United States.; Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD, United States.; School of Nursing, University of Pennsylvania, Philadelphia, PA, United States.; College of Medicine, University of Tennessee, Memphis, TN, United States.; Department of Pharmacology and Molecular Science, Johns Hopkins School of Medicine, Baltimore, MD, United States.; Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, MD, United States.; Department of Medicine, Division of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore, MD, United States.; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, United States.; Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD, United States.; Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, United States.; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, United States.; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, United States.; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States.; Lieber Institute for Brain Development, Baltimore, MD, United States. [email protected].; Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, United States. [email protected].; Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD, United States. [email protected].; Department of Pharmacology and Molecular Science, Johns Hopkins School of Medicine, Baltimore, MD, United States. [email protected].

DOI: 10.1038/s41398-020-01066-z

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MeSH Terms: Calcium Channel Blockers, Healthy Volunteers, Humans, Male, Memory, Short-Term, Nimodipine, Prefrontal Cortex, Schizophrenia