Brain histamine and oleoylethanolamide restore behavioral deficits induced by chronic social defeat stress in mice

Maurizio Casarrubea, Andrea Santangelo, Adele Romano, Alessia Costa, Justyna Barbara Koczwara, Barbara Rani, Marzia Friuli, Gustavo Provensi, Maria Beatrice Passani, Silvana Gaetani, Patrizio Blandina

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)100317-
Number of pages11
JournalNeurobiology of Stress
Publication statusPublished - 2021

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Endocrinology
  • Endocrine and Autonomic Systems
  • Cellular and Molecular Neuroscience


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