Effects of co-administration of a selective serotonin reuptake inhibitor and monoamine oxidase inhibitors on 5-HT-related behavior in rats
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.
References (27)
- et al.
Possible mechanisms of action of (−) deprenyl and other MAO-B inhibitors in some neurologic and psychiatric disorders
Prog. Neurobiol.
(1994) - et al.
Multiple populations of serotonin receptors may modulate the behavioral effects of serotonergic agents
Life Sci.
(1991) - et al.
5-HT and motor control: a hypothesis
Trends Neurosci.
(1993) - et al.
Central serotonergic responses and behavioral adaptation to repeated immobilization: the effect of the corticosterone synthesis inhibitor metyrapone
Eur. J. Pharmacol.
(1985) - et al.
Effects of risperidone on phencyclidine-induced behaviors: comparison with haloperidol and ritanserine
Jpn. J. Pharmacol.
(1994) - et al.
Effects of the novel 5-HT1A receptor antagonist, (+)-WAY 100135, on stereotyped behaviour induced by the NMDA receptor antagonist dizocilpine in rats
Eur. J. Pharmacol.
(1993) - et al.
A 5-HT2 receptor mediates serotonin-induced electrolyte transport in rat left colon
J. Surg. Res.
(1993) - et al.
Differential effects of 5-hydroxytryptamine1A selective drugs on the 5-HT behavioral syndrome
Pharmacol. Biochem. Behav.
(1986) - et al.
MAOIs in the contemporary treatment of depression
Neuropsychopharmacology
(1995) - et al.
cDNA cloning of human liver monoamine oxidase A and B: molecular basis of differences in enzymatic properties
Proc. Natl. Acad. Sci. U. S. A.
(1988)
In vivo evidence for the reversible action of the monoamine oxidase inhibitor brofaromine on 5-hydroxytryptamine release in rat brain
Naunyn-Schmiedeberg's Arch. Pharmacol.
Trace amines: identification of a family of mammalian G protein-coupled receptors
PNAS
Monoamine oxidase inhibitors increase preferentially extracellular 5-hydroxytryptamine in the midbrain raphe nuclei
Naunyn-Schmiedeberg's Arch. Pharmacol.
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