Pharmacological characterisation of the decrease in 5-HT synthesis in the mouse brain evoked by the selective serotonin re-uptake inhibitor citalopram

Abstract

The selective serotonin re-uptake inhibitor (SSRI) citalopram decreases the synthesis of 5-hydroxytryptamine (5-HT) in the mouse brain in vivo. The underlying mechanism was studied by recording the accumulation of 5-hydroxytryptophan (5-HTP) in hypothalamus and hippocampus after inhibition of the aromatic amino acid decarboxylase activity with m-hydroxybenzylhydrazine (NSD 1015). Depletion of 5-HT with reserpine markedly reduced the citalopram-induced decrease of 5-HTP but not that evoked by the 5-HT1A receptor agonist 8-OH-DPAT, which indicates that the presence of endogenous 5-HT is necessary for full effect of citalopram. In contrast to the almost complete antagonism of the decrease in 5-HT synthesis induced by 8-OH-DPAT, the 5-HT1A receptor antagonist WAY-100,635 only slightly affected the citalopram-evoked decrease in 5-HT synthesis. Likewise, the 5-HT1B receptor antagonists NAS-181 and GR127935 only slightly antagonised the citalopram effect although they strongly inhibited the decrease in 5-HT synthesis induced by the 5-HT1B receptor agonist anpirtoline. Combined treatment with 5-HT1A and 5-HT1B receptor antagonists did not produce any additive antagonistic effect on the citalopram-induced decrease in 5-HT synthesis. The 5-HT2A/2C receptor antagonist ketanserin, the 5-HT3 receptor antagonist ondansetron and the 5-HT4 receptor antagonist RS-39604 had no effect on the citalopram-induced decrease in 5-HT synthesis. The same was found for several other non-selective 5-HT receptor antagonists, e.g. cyproheptadine, dihydroergotamine, methiothepin, methysergide, metergoline and mianserin. It is concluded that the citalopram-induced decrease in 5-HT synthesis differs in sensitivity from that mediated by 5-HT1A or 5-HT1B receptor agonists and citalopram also seems to require endogenous 5-HT for its full effect.

Analysis of the Role of the 5-HT1B Receptor in Spatial and Aversive Learning in the Rat

“…This suggests that the effects of anpirtoline on cognition are mediated by stimulation of the 5-HT 1B receptor. This is consistent with biochemical studies showing that NAS-181 can fully block the decrease in 5-HT synthesis induced by anpirtoline in the mouse (Stenfors et al, 2001).…”

Genotype-Dependent Activity of Tryptophan Hydroxylase-2 Determines the Response to Citalopram in a Mouse Model of Depression

“…Because the inhibition of 5-HT synthesis by citalopram is reversed by 5-HT 1A and 5-HT 1B/1D receptor antagonists (Barton and Hutson, 1999), it has been suggested that autoreceptor activation plays a major role. However, other studies failed to con- firm this and suggested that some other 5-HT receptor subtype contributes (Moret and Briley, 1997;Stenfors et al, 2001). Interestingly, TRP and the activation of TPH by Ca/calmodulin kinase II and protein kinase A enhanced 5-HT 1A receptor-mediated inhibition of dorsal raphe 5-HT neurons (Liu et al, 2005).…”

“…SSRI-induced inhibition of 5-HT synthesis depends on the ability of the drugs to enhance endogenous 5-HT tone on 5-HT receptors, which in turn inhibits 5-HT synthesis (Stenfors et al, 2001). Because the inhibition of 5-HT synthesis by citalopram is reversed by 5-HT 1A and 5-HT 1B/1D receptor antagonists (Barton and Hutson, 1999), it has been suggested that autoreceptor activation plays a major role.…”

Toward a better understanding of depression and anxiety: the involvement of stress and tryptophan hydroxylase activation

“…At the dose required to inhibit decarboxylase (100 mg/kg ip) in rats, NSD 1015 activates the synthesis of 5-HT by up to 52% depending upon the brain region [Muck-Seler and Diksic, 1995]. Although alternative and possibly more selective amino-acid decarboxylase inhibitors have been described [e.g., Palfreyman et al, 1984], NSD 1015 is still used routinely to block the decarboxylation of 5-hydroxytryptophan (5-HTP) in order to measure its rate of accumulation in the presence and absence of transmitter reuptake inhibitor antidepressants, e.g., citalopram [Stenfors et al, 2001]. All of these antidepressants decrease 5-HT turnover measured by this method (15-50%), which is generally believed to reflect a 5-HT postsynaptic induced negative feedback regulation of 5-HT synthesis [Corrodi and Fuxe, 1969;Carlsson and Lindqvist, 1978].…”