Serotoninergic Reuptake Mechanisms in the Control of Cataplexy

Abstract

Summary: Zimelidine, a selective inhibitor of serotonin (5-HT) reuptake in the CNS, was administered to narcoleptic patients. This medication has a potent anticataplectic action without improving daytime somnolence. These results suggest that 5-HT neuronal systems are involved in the physiopathology of cataplexy. Zimelidine, however, has no anticholinergic effect, so it is unlikely that cholinergic mechanisms thought to be important in animal cataplexy would playa major role in human cataplexy. In addition, zimelidine had no effect on nocturnal sleep patterns of these patients which is surprising considering the importance of 5-HT neuronal systems in sleep physiology. A 5-HT hypothesis of cataplexy is formulated, and the mechanisms of action of other anticataplectic agents are discussed.Key Words: Narcolepsy-Cataplexy-Serotonin-Zimelidine-Myoclonus.Narcoleptic patients complain of two major symptoms, namely, excessive daytime sleepiness (EDS) and cataplexy. Clinical data suggest that different mechanisms are involved in these two symptoms. In most patients, EDS and cataplexy do not develop simultaneously, and there is no correlation between the intensity of the two symptoms. Pharmacological studies also suggest that different mechanisms are involved. For instance, drugs known to improve EDS have little or no effect on cataplexy, and, conversely, most anticataplectic medications do not relieve the complaint of EDS (1).In humans, EDS most likely involves dopaminergic mechanisms in the central nervous system (CNS). For instance, low concentrations of free dopamine (DA) (2) and of homovanillic acid (HVA) (3), the main metabolite of DA, were found in the cerebrospinal fluid (CSF) of narcoleptic patients. In addition, psychostimulants effective to treat daytime sleepiness selectively decrease DA reuptake (4).The pathophysiology of cataplexy is more controversial. In humans, most data come from pharmacological studies (5). Although there is no controlled study comparing the potency of various anticataplectic agents, our clinical experience indicates that chlorimipramine is the most effective medication. Among anticataplectic agents, chlorimipramine also happens to be the most potent 5-HT reuptake blocker (6). We hypothesize that this mechanism is responsible for the anticataplectic action of this medication. However, chlorimipramine has also a strong anticholinergic action, and desmethylchlorimipramine, its main metabolite, is a norepinephrine (NE) reuptake blocker in the CNS. The anticholinergic

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“…Various neurochemical abnormalities have been identified, involving the monoamines noradrenaline (norepinephrine), dopamine and serotonin (Faull et a/. 1982;Montpalaisir and Godbout 1986;Bowersox et a / . 1987), and also levels of cholinergic receptors Siege1 et a/.…”

Freezing of Gait in Parkinson's Disease is Improved by Treatment with Weak Electromagnetic Fields

“…Cataplexy is characterised by immobility and sudden loss of muscle tone resulting in falling usually brought on by sudden excitement or emotional influences (Scrima, 1981). Cataplexy probably results from inadequate 5-HT and norepinephrine inhibition of cholinergic-controlled REM sleep mechanisms and is inhibited by 5-HT reuptake inhibitors (Amatruda et al, 1975;Aldrich, 1993;Montplaisir & Godbout, 1986;Frey & Darbonne, 1994). Cataplexy probably results from inadequate 5-HT and norepinephrine inhibition of cholinergic-controlled REM sleep mechanisms and is inhibited by 5-HT reuptake inhibitors (Amatruda et al, 1975;Aldrich, 1993;Montplaisir & Godbout, 1986;Frey & Darbonne, 1994).…”