Abstract
The physiological mechanisms underlying the complex interplay between life stressors and metabolic factors is receiving growing interest and is being analyzed as one of the many factors contributing to depressive illness. The brain histaminergic system modulates neuronal activity extensively and we demonstrated that its integrity is necessary for peripheral signals such as the bioactive lipid mediator oleoylethanolamide (OEA) to exert its central actions. Here, we investigated the role of brain histamine and its interaction with OEA in response to chronic social defeat stress (CSDS), a preclinical protocol widely used to study physio-pathological mechanisms underlying symptoms observed in depression. Both histidine decarboxylase null (HDC−/-) and HDC+/+ mice were subjected to CSDS for 21 days and treated with either OEA or vehicle daily, starting 10 days after CSDS initiation, until sacrifice. Undisturbed mice served as controls. To test the hypothesis of a histamine-OEA interplay on behavioral responses affected by chronic stress, tests encompassing the social, ethological and memory domains were used. CSDS caused cognitive and social behavior impairments in both genotypes, however, only stressed HDC+/+ mice responded to the beneficial effects of OEA. To detect subtle behavioral features, an advanced multivariate approach known as T-pattern analysis was used. It revealed unexpected differences of the organization of behavioral sequences during mice social interaction between the two genotypes. These data confirm the centrality of the neurotransmitter histamine as a modulator of complex behavioral responses and directly implicate OEA as a protective agent against social stress consequences in a histamine dependent fashion.
Highlights
Histamine and OEA are phylogenetically old molecules that have been described in several species, from Drosophila (Tortoriello et al, 2013) (Denno et al, 2016) to humans (Schaefer et al, 2014) (Panula and Nuutinen, 2013)
The physiological role of these effects have been extensively demon strated as OEA releases oxytocin to induce satiety (Gaetani et al, 2010) and we previously demonstrated that this occurs in a histamine-dependent way (Provensi et al, 2014; Umehara et al, 2016)
Bonferroni’s post hoc analysis revealed that non-stressed HDC− /- mice treated with vehicle ate significantly less than nonstressed and stressed mice treated with OEA and stressed mice treated with vehicle of both genotypes
Summary
Histamine and OEA are phylogenetically old molecules that have been described in several species, from Drosophila (Tortoriello et al, 2013) (Denno et al, 2016) to humans (Schaefer et al, 2014) (Panula and Nuutinen, 2013). They interact directly or indirectly to control metabolic (Misto et al, 2019) as well as behavioural responses (Costa et al, 2018; Provensi et al, 2017). The hista minergic neurotransmission serves as a gateway for OEA to exert cognitive effects in contextual fear memory (Provensi et al, 2017) and antidepressant-like effects in an acute stress based model, the tail sus pension test (Benetti et al, 2015; Costa et al, 2018; Provensi et al, 2014). Recent evidence suggests that OEA de creases frustration stress-induced binge-like eating in female rats (Romano et al, 2020), further supporting the potential beneficial effect of OEA in stress-conditions
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