Histaminergic transmission potentiates post-traumatic stress-induced expression of anxiety in mice

Post-traumatic stress is associated with an increased expression of anxiety traits and is reported to be accompanied by altered brain histamine content. However, the contribution of the central histaminergic system in the stress induced anxiety, still remains unclear. Therefore, the present study explored the plausible role of central histaminergic transmission in stress-induced anxiety measures in mice using LDB test and in the expression of CORT, CREB, or BDNF levels in the whole brain, PFC, amygdala, and hippocampus of mice. The mice were exposed to the SPS protocol and subsequently left undisturbed for 7 days. On the 8th day, non-SPS/SPS exposed mice were treated i.c.v with histaminergic agents such as histamine, or histamine precursor, l-histidine, H₁ agonist, FMPH, H₂ agonist, amthamine, H₁ antagonist, cetirizine or H₂ antagonist, ranitidine or H₃ inverse agonist, thioperamide and thereafter evaluated for changes in expression of anxiety followed by estimation of CORT, CREB and BDNF levels in brain. Results revealed that SPS-exposed mice elicit heightened anxiety-like behavior accompanied by increased levels of blood or brain histamine and CORT with reduced BDNF/CREB expression in the all-brain tissues. Administration of histaminergic enhancing agents to SPS-exposed mice potentiated the higher expression of anxiety, also further enhanced CORT, and diminished the BDNF/CREB expression in all brain regions. Conversely, central injection of the H₁ receptor antagonist, cetirizine (0.1 μg/mouse) or H₂ receptor antagonist, ranitidine (10 μg/mouse, i.c.v) to SPS mice completely alleviated all the stressed induced changes while H₃ receptor inverse agonist, thioperamide (2, 10 μg/mouse) failed to affect CORT but restored basal anxiety, CREB and BDNF expression. Thus, the blockade of central histamine H₁/H₂/H₃ receptors might mitigate SPS-induced anxiety-like manifestations by extenuating the SPS-induced CORT, CREB, and BDNF expression.