Chronic but not acute pharmacological activation of SERCA induces behavioral and neurochemical effects in male and female mice

Intracellular calcium (CA²⁺) homeostasis is a vital process to nerve cell survival and function with an intricate regulatory network. It is well established that the endoplasmic reticulum (ER) is a major intraneuronal CA²⁺ storage and that the sarco/endoplasmic reticulum (SR/ER) calcium (CA²⁺)-ATPase (SERCA) pump is a key regulator of cytosolic CA²⁺ levels. SERCA pumps play a critical role in brain pathophysiology, thus SERCA comprises an emerging pharmacological target for the treatment of brain diseases. Interestingly, preclinical studies in rodents suggest that chronic pharmacological activation of SERCA2 by the quinoline derivative CDN1163 comprises a potential pharmacotherapeutic target in Alzheimer's and Parkinson's diseases. As little is known about the behavioral and neurochemical consequences of CDN1163 administration, in the current study we investigated the potential effects of acute (i.e., at 1 h) and chronic (i.e., 17 days) CDN1163 administration (i.e., 10 mg/kg and 20 mg/kg; intraperitoneally) on locomotor activity and relevant affective behaviors, as well as on monoaminergic neurotransmission in naïve C57BL/6J mice of both sexes. Interestingly, chronic, but not acute, CDN1163 administration induced anxiogenic and depressive-like behavioral effects in mice, as assessed in the open field (OF) test and the forced swim test (FST), respectively. In addition, chronic CDN1163 administration induced sustained sex- and brain region-dependent noradrenergic and serotonergic neurochemical effects ex vivo. Taken together, present findings support the critical role of SERCA-dependent CA²⁺ handling in regulating behavior and neurochemical activity, and further highlight the need to consider sex in the development of SERCA-targeting pharmacotherapies for the treatment of debilitating brain disorders.