Effects of co-administration of a selective serotonin reuptake inhibitor and monoamine oxidase inhibitors on 5-HT-related behavior in rats

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Abstract

5-hydroxytryptamine (5-HT) syndrome is a dangerous condition of 5-HT excess that can occur in the case of co-administration of a monoamine oxidase (MAO) inhibitor and a serotonin reuptake inhibitor (SSRI). The goal of the present study was to investigate the effects of acute administration of MAO inhibitors and subchronic administration of fluvoxamine on 5-HT-related behaviors (head shaking and 5-HT syndrome) in rats treated with 5-hydroxytryptophan (5-HTP). Administration of the non-selective MAO inhibitor, pargyline, and the selective MAO-A inhibitor, clorgyline, resulted in 5-HT syndrome in 5-HTP-treated rats, and subchronic co-administration of fluvoxamine intensified the syndrome. However, administration of the selective MAO-B inhibitor, selegiline, did not induce 5-HT syndrome with or without subchronic fluvoxamine co-administration. These data suggest that non-selective MAO and selective MAO-A inhibitors can induce 5-HT syndrome in humans when co-administered with SSRI. Further, the risk of 5-HT syndrome may be lower with the selective MAO-B inhibitor, selegiline.

Introduction

Monoamine oxidase (MAO) inhibitors have been used for the treatment of depression since the 1950s and may be particularly useful for treatment of tricyclic antidepressant-resistant depression (Thase et al., 1995). However, the use of MAO inhibitors has been limited by the potential for a hypertensive reaction induced by interaction between MAO inhibitor and tyramine in food and by the various neuropsychiatric symptoms induced by co-administration of a MAO inhibitor and a tricyclic antidepressant (White and Simpson, 1981, Kennedy et al., 2000).

There are two different isoforms of the MAO enzyme: isoform A and isoform B (Bach et al., 1988). MAO-A functions to deaminate 5-hydroxytryptamine (5-HT), norepinephrine, tyramine, and dopamine, while MAO-B mainly deaminates trace amines (i.e., benzylamine, phenylethylamine, tyramine) and dopamine (Luique et al., 1995). Although classic MAO inhibitors irreversibly and non-selectively bind to MAO-A and B, reversible or selective MAO inhibitors, such as moclobemide and brofaromine (MAO-A inhibitors), have been developed and are effective in treating depressive disorders (Fulton and Benfield, 1996, Kennedy et al., 2000).

Because tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRI) exert their antidepressive effect by inhibiting reuptake of norepinephrine or 5-HT, past studies have suggested that the antidepressant effects of MAO inhibitors are mediated by inhibition of MAO-A rather than by inhibition of MAO-B (Thase et al., 1995). However, other studies have demonstrated the efficacy of the MAO-B inhibitor, selegiline, in patients with depressive disorders. Indeed, while many investigators have demonstrated that selegiline was effective when given in high non-selective doses (≥ 30 mg/day), a few studies have also demonstrated that selegiline has efficacy when given in low MAO-B selective doses (5–10 mg/day) (Berry et al., 1994, Sunderland et al., 1994). These data suggest that the antidepressant effect of selegiline may be mediated by inhibition of norepinephrine or 5-HT deamination as well as by inhibition of dopamine deamination. Further, other studies suggest that the antidepressant effect of selegiline may also be mediated by inhibition of trace amine-deamination (Borowsky et al., 2001).

These data suggest that the new class of selective MAO inhibitors may be of clinical utility for the treatment of depression, particularly in patients that have failed other therapy. However, the risk of developing 5-HT syndrome in response to this new class of drugs has not been fully examined. This is particularly relevant, as the risk of accidental co-administration of these new MAO inhibitors with SSRI treatment is not insignificant. Therefore, the goal of the present study was to investigate the effect of administration of a MAO inhibitor (an irreversible nonselective MAO inhibitor, pargyline; an irreversible selective MAO-A inhibitor, clorgyline; or an irreversible selective MAO-B inhibitor, selegiline) and concomitant subchronic administration of a SSRI (fluvoxamine) on 5-HT-related behavior in rats treated with 5-hydroxytryptophan (5-HTP).

Section snippets

Materials and methods

The study was approved by the Hokkaido University Graduate School of Medicine Animal Care and Use Committees.

Experiment 1 (head shaking behavior)

Following 5-HTP injection, head shaking behavior was present in rats given saline or selegiline after 5-HTP injection, but both groups showed no significant difference in head shaking counts during any observation period. Head shaking behavior was not present in rats given pargyline or clorgyline (data not shown).

Experiment 2 (5-HT syndrome/dose–response, Tables 1A–C)

5-HT syndrome was rarely observed in the saline control group. Doses of 20, 25, 30 and 75 mg/kg of pargyline elicited forepaw treading, hind limb abduction, straub tail and tremor, and

Discussion

In experiment 1, administration of 2 mg/kg of selegiline resulted in no intensification of 5-HTP-induced head shaking behavior. By contrast, administration of 75 mg/kg of pargyline or 2 mg/kg of clorgyline induced intense 5-HT syndrome in 5-HTP-treated rats, but head shaking behavior was not observed. Head shaking behavior is mediated by stimulation of the 5-HT2A receptor (Willins and Meltzer, 1997), while 5-HT syndrome in rats is mediated by stimulation of the 5-HT1A receptor (Lucki et al.,

Acknowledgements

This study was supported by Japanese Ministry of Education grants No. 05454308 (T. K.) and No. 06770740 (T. I.) and Itoh Foundation.

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