SSRIs are mainstays in treatment of depression, and their highly specific actions enhancing 5-HT neurotransmission appears to explain their safety profile. Despite their claimed selectivity, however, SSRIs interact, either directly or indirectly, with various neurotransmitter systems. The tuberomammillary nucleus (TMN) is the only source of histamine (HA) fibers, and receives serotonergic inputs from the raphé. To learn whether SSRIs affect the activity of HA neurons, citalopram was administered to rats and HA release was determined by microdialysis. SD male rats (250 g) were implanted with one probe in the TMN, and one in either the nucleus basalis magnocellularis or nucleus accumbens. HA output from the two probes, perfused with Ringer at 2-ml/min, was measured in 15-min samples by HPLC-fluorometric detection. Rats were conscious and moved freely in the cage. Spontaneous HA release from all regions was stable, ranging 0.05-0.08 pmol/15min (N=17). Intra-TMN administration of citalopram (1-10 mM) for 60 min increased significantly HA release up to about 100% of basal value from all areas (P<0.05, ANOVA/Fisher's test). Pretreatment with methysergide (10 mM), a 5-HT2 receptor antagonist, completely abolished the effect of 10 mM citalopram. These results suggest that citalopram activates HA neurons by increasing the extracellular levels of endogenous 5-HT, and provide evidence of functional connections between HA and 5-HT neuronal systems. Accordingly, earlier studies reported that local perfusion with 5-HT increased HA release from the anterior hypothalamus in anesthetized rats [1], and that 5-HT depolarized HA neurons [2]. Some effects elicited by SSRI may rest on the interaction of 5-HT with the histaminergic system. Mice unable to synthesize histamine due to targeted disruption of the histidine decarboxylase (HDC) gene were used to critically test histamine role in mediating acute behavioural changes elicited by citalopram or reboxetine. To this end, we used the tail suspension test in WT and HDC-KO mice. Both citalopram (SSRI) and reboxetine (NSRI) reduced immobility in WT mice. Reboxetine was effective at reducing immobility also in HDC-KO mice, which, surprisingly, failed to respond to the behavioural effects of citalopram. These data show that histamine plays an important role in mediating acute behavioural and neurochemical actions of citalopram , the most selective SSRI.

[1] Laitinen et al., Eur J Pharmacol 1995; 285:159-164.

[2] Erikson et al., Neuropharmacology 2001; 40:345-351.

Supported by PRIN2007-519-MIUR-068