IS BRAIN HISTAMINE INVOLVED IN DEPRESSION?

Mice unable to synthesize histamine, due to targeted disruption of histidine decarboxylase (HDC) gene or i.c.v. injection of alpha-fluoromethylhistidine (a-FMH, 5 lg), a suicide inhibitor of HDC, were used to test roles for histamine in mediating behavioural changes elicited by different classes of antidepressants, selective serotonin reuptake inhibitors (SSRI) such as citalopram and paroxetine or selective noradrenaline reuptake inhibitors (SNRI), such as reboxetine. The tail suspension test (TST) which is a widely used paradigm for assessing antidepressant activity was used. Both classes of antidepressants reduced immobility in controls [wild type (WT) mice for HDC-KO mice, and saline-injected CD-1 mice for a-FMHtreated CD-1 mice (n = 11–18)]. HDC-KO mice as well as a-FMH-treated CD-1 mice failed to respond to acute injections of citalopram (10 mg/kg, i.p.) or paroxetine (10 mg/kg, i.p.) with a reduction of immobility. Conversely, reboxetine (5 mg/ kg, i.p.) reduced immobility in both WT and HDC-KO mice (p\0.0001). Since the histaminergic tuberomammillary nucleus receives 5-HT inputs from the raphe´, we investigated whether SSRIs affect histamine release. CD-1 male mice (*30 g) were implanted with amicrodialysis probe in the prefrontal cortex. After 48 h recovery, the probe was perfusedwith Ringer’s solution (1 ll/min) and dialysates were collected every 30 min. Histamine was detected by HPLC-fluorometric detection. Spontaneous histamine release was 0.058 ± 0.006 pmol/30 min (n = 6). Citalopram (10 mg/kg; i.p.) increased HA up to more than 50% of basal value. 5-HT transmission appears intact in HDC-KO mice, since local infusion of citalopram (50 lM) into the hippocampus of HDCKO mice increased by more than 100% the basal release of 5-HT, as measured by microdialysis. These data show that the central histamine system plays an important role in mediating acute behavioural and neurochemical actions of citalopram.