J.-M. Stutzmann

Riluzole promotes survival of rat motoneurons in vitro by stimulating trophic activity produced by spinal astrocyte monolayers.

In the present study we have assessed whether riluzole stimulates the production of trophic activities for motoneurons by spinal astrocyte cultures. Astrocyte monolayers prepared from new-born rats were exposed to vehicle or riluzole (1-10 microM) for 30-36 h, then washed and further incubated without riluzole for 24 h in L15 medium to obtain the astrocyte conditioned media (ACM). Motoneuron-enriched cultures were used to test the ability of the ACM to support motoneuron viability. Astrocyte monolayers exposed to 1 microM riluzole did not show changes in morphology or in DNA or protein synthesis. However, the conditioned medium obtained from astrocyte monolayers after this treatment increased motoneuron survival compared to that from vehicle-treated cultures. A similar effect was found when astrocytes were exposed to a higher riluzole concentration (10 microM) but with greater dilutions of the conditioned medium. This trophic activity was abolished by boiling or after treatment with trypsin. These findings strongly suggest the existence of a new trophic mechanism, through which riluzole may exert motoneuron protection.

Effect of riluzole on quinolinate-induced neuronal damage in rats: comparison with blockers of glutamatergic neurotransmission

Intrastriatal injection of quinolinate, an N-methyl-D-aspartate (NMDA) agonist, induces a local neuronal lesion, and provides an excitotoxic model of Huntingtons disease. In this study, we investigated the effect of different agents acting at various levels of the glutamatergic neurotransmission: (i) dizocilpine (MK801) (0.5 mg/kg ip) significantly reduced the lesion by 74%; (ii) 6-(1-imidazolyl)-7-nitroquinoxaline-2,3(1H,4H)-dione (YM-90K) (3 x 10 and 3 x 20 mg/kg ip) and (iii) lamotrigine (50 mg/kg ip) had no effect; (iv) riluzole (4 and 8 mg/kg per os) significantly reduced the lesion by 35%. The inefficiency of YM-90K suggested that alpha-amino-3-hydroxy-5-methylisoxasole-4-propionate (AMPA) receptors do not participate to the quinolinate-induced excitotoxicity. The mechanism of action of riluzole may be related also to a combination of its different properties. This study indicates that riluzole may be useful for treatment of Huntingtons disease.

Are 5-HT2 antagonists endowed with anxiolytic properties in rodents?

The precise role of serotonin (5-HT) in anxiety remains unclear. We report here on the effects of RP 62203, a new 5-HT2 antagonist, and ritanserin in different animal models of anxiety. In the elevated plus-maze in mice, RP 62203 increased dose-dependently the percentage of entries onto, and time spent on open arms, over the dose range 0.25-4 mg.kg-1 p.o. By contrast, ritanserin was ineffective up to the dose of 4 mg.kg-1 p.o. In addition, both compounds were tested against the anxiogenic compound FG 7142 (20 mg.kg-1, i.p.) in the plus-maze test in mice and via electrocorticographic recordings (ECoG) in rats. The anxiolytic effect of RP 62203 is antagonized by FG 7142 at a dose devoid of anxiogenic properties. A similar interaction between RP 62203 and FG 7142 is observed in ECoG studies. In contrast, ritanserin seemed to potentiate the anxiogenic and awakening activities of FG 7142. These results demonstrate that RP 62203, a selective 5-HT2 antagonist, possesses anxiolytic properties in rodents suggesting that 5-HT2 receptors are involved in the control of anxiety.

Riluzole, a glutamate antagonist, enhances slow wave and REM sleep in rats

Riluzole is a drug that interferes with glutamate neurotransmitters. We studied the sleep pattern of rats treated orally with riluzole at doses ranging from 0.5 to 8 mg/kg. Duration of slow wave sleep and rapid eye movement sleep was found to increase in a dose-dependent manner from 1 mg/kg, at the expense of awakeness. These data suggest that glutamate neurotransmission may be involved in the regulation of sleep. Riluzole can be of interest as sleep modulator, in particular in psychiatric disorders.

Cyclopyrrolones unlike some benzodiazepines do not induce physical dependence in mice

In a model of physical dependence in mice, treatment with cyclopyrrolones such as zopiclone and suriclone (from 4 to 400 mg/kg/day), did not modify the sensitivity of the gamma-aminobutyric acid (GABA) receptor complex to the partial inverse agonist FG 7142 following their withdrawal, whereas sensitivity changes were observed after treatment and withdrawal from some benzodiazepines (e.g. lorazepam, diazepam, flunitrazepam and triazolam). These data suggest that, in contrast to some benzodiazepines, zopiclone and suriclone may not produce physical dependence.