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bioRxiv · 10.1101/2025.09.05.674525

Cross-Species Evidence for Hippocampal CACNA1C as a Therapeutic Target for Alcohol Use Disorder

Pareek, T.·Pham, L. M.·O'Donovan, S. M.·Zamarripa, C. A.·Allen, O.·Freeman, K. B.·Platt, D. M.·Grant, K. A.·Pantazopoulos, H.·Gisabella, B.
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Abstract

Context-induced relapse is a major barrier to recovery from alcohol use disorder (AUD). Identifying molecular targets involved in contextual memories associated with alcohol use may serve as novel pharmacotherapies. Our RNAseq profiling study of the hippocampus from rhesus monkeys with chronic alcohol use identified the voltage-gated calcium channel CACNA1C as a promising therapeutic target. However, data regarding CACNA1C expression in AUD and whether inhibition of CACNA1C can attenuate ethanol contextual memories remains limited. We tested the hypothesis that hippocampal CACNA1C expression is increased in human and nonhuman primates (NHPs) with chronic alcohol use. Further, we used a mouse conditioned place preference (CPP) paradigm to test the hypothesis that Nifedipine, a CACNA1C-selective L-type calcium channel antagonist, can attenuate ethanol-induced CPP. CACNA1C mRNA expression was increased in the hippocampus of subjects with AUD (p<0.03). Increased densities of CACNA1C neurons (p<0.01) and glia (p<0.02) were observed in rhesus monkeys with chronic alcohol use. Ethanol-treated mice spent more time in the ethanol-paired chamber compared to the vehicle animals (p<0.04), demonstrating ethanol-induced CPP. This effect was attenuated by Nifedipine, as time spent in the ethanol-paired chamber in the ethanol + Nifedipine group was not significantly different from the vehicle group. These findings demonstrate that chronic alcohol use increases CACNA1C expression in the hippocampus across species and that a CACNA1C subtype-selective antagonist reduces ethanol-induced CPP. Together, these results support CACNA1C as a promising therapeutic target for context-induced relapse in AUD.

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Pareek, T., Pham, L. M., O'Donovan, S. M., Zamarripa, C. A., Allen, O., Freeman, K. B., Platt, D. M., Grant, K. A., Pantazopoulos, H., Gisabella, B.. 2025-09-05. Cross-Species Evidence for Hippocampal CACNA1C as a Therapeutic Target for Alcohol Use Disorder. https://doi.org/10.1101/2025.09.05.674525

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