Brain Histamine Is Crucial for Selective Serotonin Reuptake Inhibitors‘ Behavioral and Neurochemical Effects

Abstract

Backgound:The neurobiological changes underlying depression resistant to treatments remain poorly understood, and failure to respond to selective serotonin reuptake inhibitors may result from abnormalities of neurotransmitter systems that excite serotonergic neurons, such as histamine.Methods:Using behavioral (tail suspension test) and neurochemical (in vivo microdialysis, Western-blot analysis) approaches, here we report that antidepressant responses to selective serotonin reuptake inhibitors (citalopram or paroxetine) are abolished in mice unable to synthesize histamine due to either targeted disruption of histidine decarboxylase gene (HDC-/-) or injection of alpha-fluoromethylhistidine, a suicide inhibitor of this enzyme.Results:In the tail suspension test, all classes of antidepressants tested reduced the immobility time of controls. Systemic reboxetine or imipramine reduced the immobility time of histamine-deprived mice as well, whereas selective serotonin reuptake inhibitors did not even though their serotonergic system is functional. In in vivo microdialysis experiments, citalopram significantly increased histamine extraneuronal levels in the cortex of freely moving mice, and methysergide, a serotonin 5-HT1/5-HT2 receptor antagonist, abolished this effect, thus suggesting the involvement of endogenous serotonin. CREB phosphorylation, which is implicated in the molecular mechanisms of antidepressant treatment, was abolished in histamine-deficient mice treated with citalopram. The CREB pathway is not impaired in HDC-/- mice, as administration of 8-bromoadenosine 3’, 5’-cyclic monophosphate increased CREB phosphorylation, and in the tail suspension test it significantly reduced the time spent immobile by mice of both genotypes.Conclusions:Our results demonstrate that selective serotonin reuptake inhibitors selectively require the integrity of the brain histamine system to exert their preclinical responses.

Memory retrieval of inhibitory avoidance requires histamine H 1 receptor activation in the hippocampus

“…We suggest that increased levels of pCREB are required for the retrieval of IA-LTM through activation of H 1 receptors. Consistently, earlier reports indicate that histamine signaling is necessary to trigger CREB phosphorylation in the hippocampus (17,57). The hippocampus is involved in both the aversive component of the IA and its contextual aspect as reviewed in the work by Izquierdo et al (58).…”

G protein‐coupled oestrogen receptor stimulation ameliorates iron‐ and ovariectomy‐induced memory impairments through the cAMP/PKA/CREB signalling pathway

“…The densitometric quantification was performed using a chemiluminescent photo finder (Carestream, model GL2200; Kodak, Rochester, NY, USA). pCREB densities were divided by their respective CREB densities within each sample to obtain pCREB:CREB ratio values …”

Donepezil, an acetylcholine esterase inhibitor, and ABT-239, a histamine H3 receptor antagonist/inverse agonist, require the integrity of brain histamine system to exert biochemical and procognitive effects in the mouse

“…We recently showed that i.c.v. infusion of a-FMHis (5 µg/µL) M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 8 quickly and fully suppressed the release of brain histamine measured by microdialysis in mice (Munari et al, 2015) as well as in rats. CD-1 mice receiving equivalent injections of saline (i.c.v.…”