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

Chronic pharmacological activation of SERCA with CDN1163 affects spatial cognitive flexibility but not attention and impulsivity in mice

“…Overall, it could be speculated that enhanced endoplasmic reticular Ca 2+ load induced by CDN1163-mediated SERCA activation may alter synaptic plasticity and neuronal signaling processes; this could ultimately result in the manifestation of impaired cognitive flexibility observed during assessment of reversal learning and memory in the MWM. In the context of our previously published study, chronic CDN1163 treatment induced sex-specific serotonergic neurochemical alterations in the striatum of male and female mice, a brain region involved in cognition and executive functioning (Prado-Alcalá et al, 2003;Kenton et al, 2008;Zhukovsky et al, 2017;Britzolaki et al, 2021). Indeed, studies in rats and nonhuman primates have demonstrated that the striatal circuitry participates in the regulation of reversal memory and cognitive flexibility (Clarke et al, 2008;Braun and Hauber, 2011;Izquierdo et al, 2017;Bergstrom et al, 2020).…”

“…CDN1163 (20 mg/kg, MedChemExpress LLC, New Jersey, USA) was dissolved in a VEH solution of 10% dimethyl sulfoxide and 90% corn oil and delivered intraperitoneally (i.p. ), as described in our previous study (Britzolaki et al , 2021). A 20 mg/kg chronic CDN1163 dosage scheme was employed in the current study based on our previous findings that this treatment regimen induced both behavioral effects and robust neurochemical alterations in brain regions implicated in the neurobiology of learning, memory and cognitive function (Britzolaki et al , 2021).…”

“…), as described in our previous study (Britzolaki et al , 2021). A 20 mg/kg chronic CDN1163 dosage scheme was employed in the current study based on our previous findings that this treatment regimen induced both behavioral effects and robust neurochemical alterations in brain regions implicated in the neurobiology of learning, memory and cognitive function (Britzolaki et al , 2021). For the MWM assessments, CDN1163 or VEH was administered for 17 days before the start of experiments and continued throughout testing.…”

“…Notably, a recent study employed a new brain-specific heterozygous deletion of the SERCA2 mouse strain that displayed deficits in fear learning, lending further support to the role of SERCA in regulating cognitive functioning (Nakajima et al , 2021). Moreover, a recent study from our lab has shown that chronic pharmacological SERCA activation using CDN1163 results in anxiogenic- and depressive-like behaviors in naïve male and female mice (Britzolaki et al , 2021). Intriguingly, we also found that these behavioral effects were accompanied by sex-specific neurochemical alterations in the brain, including disruption of the hippocampal and prefrontocortical noradrenergic systems, which have been long known to be involved in the regulation of learning, memory, and executive functioning (Del Campo et al , 2011; Bari and Robbins, 2013; Hansen, 2017; Palacios-Filardo and Mellor, 2019).…”

Sarco/endoplasmic reticulum Ca2+‐ATPase (SERCA2b) mediates oxidation‐induced endoplasmic reticulum stress to regulate neuropathic pain

“…Thus, for a perspective, CDN1163 may represent a lead compound to develop new therapies for neuropathic pain. A recent study demonstrated that chronic exposure to CDN1163 for 17 days at doses of 10 and 20 mg induced mild anxiogenic and depressive-like behavioural effects (Britzolaki et al, 2021) although the engagement of SERCA needs further investigation in such behavioural changes. Thus, due to the universal expression of SERCA2b in different tissues, and the important role in the regulation of intracellular Ca 2+ dynamics of SERCA2b, the side effect subsequent to SERCA2b activity up-regulation needs to be further explored.…”