Interactions of a non-selective monoamine oxidase inhibitor, phenelzine, with inhibitors of 5-hydroxytryptamine, dopamine or noradrenaline re-uptake

Abstract

Interactions of combined antidepressants which occur in man were reproduced in rats pretreated with phenelzine, features elicited including myoclonic phenomena, an augmented lower limb flexor reflex, muscle fassiculation and fatalities, particularly with combinations incorporating 5-hydroxytryptamine (5-HT) re-uptake inhibitors. Combinations of antidepressants included phenelzine with 5-HT re-uptake inhibitors (paroxetine, fluoxetine, clomipramine); with “mixed” re-uptake inhibitors affecting 5-HT and noradrenaline (imipramine, amitriptyline); with noradrenaline re-uptake inhibitors (desipramine, maprotiline, nisoxetine) and with dopamine re-uptake inhibitors (benztropine, nomifensine). Myoclonic phenomena such as forelimb flexor-extensor movements, head and body twitches, occured in phenelzine pretreated rats after paroxetine, fluoxetine, clomipramine, imipramine, amitriptyline and desipramine. Wet dog shakes, the most intense phenomenon, were obtained only after paroxetine, fluoxetine, clomipramine and imipramine. Myoclonic features were prevented when pretreatment included p-chlorophenylalanine but were unaffected when this incorporated α-methyl- p-tyyrosine; there were attenuated by methysergide, cyproheptadine, clozapine or pimozide. The myoclonic phenomena were reproduced by combination of 5-hydroxytryptophan but not L-3,4-dihydroxyphenylalanine with clomipramine. Electrocortical changes observed included 2–4 Hz, 5–8 Hz, large amplitude potentials unrelated to the myoclonic incidents and unaffected by sensory stimulation. Following phenelzine, brain monoamine oxidase (MAO) A inhibition was 99% and that of MAO B, 88%; 5-HT concentration was significantly elevated in the cortex and hypothalamus, as was hypothalamic noradrenaline. Peak and basal tensions of a lower-limb flexor reflex were elevated in phenelzine pretreated spinal rats by fluoxetine, paroxetine, clomipramine and imipramine, effects attenuated by cyproheptadine. Forelimb flexor-extensor movements and body twitches were elicited by fluoxetine and paroxetine in phenelzine pretreated spinal rats in the presence of electrical stimulation of the central stump of a divided posterior tibial nerve. Pressor responses were observed in phenelzine pretreated spinal rats given 5-HT re-uptake inhibitors, “mixed” re-uptake inhibitors and those affecting noradrenaline re-uptake; ECG anomalies occured in such rats given clomipramine.