Effect of Timiperone, a New Drug, on the Sleep-Wakefulness Cycle in Cats

Makoto TANAKA, Hiroshi KOJIMA and Akira AKASHI

Laboratory of Pharmacology, Research Institute, Daiichi Seiyaku Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134, Japan

Accepted August 22, 1985

Abstract-The effect of timiperone, a new antipsychotic drug, on the sleep wakefulness cycle in cats was assessed by EEG, EMG and eye movement potential. Timiperone (0.03 to 0.3 mg/kg, i.p.) dose-dependently increased the slow wave sleep (SWS) time and decreased the paradoxical sleep (PS) time. Further, the onset of the first period of PS was delayed, and the number of PS phases tended to he decreased after the 0.3 mg/ kg dose. These results suggest that the neurological control of the cerebral system might be at least in part attributable to the effect of timiperone on sleep mechanisms.

Timiperone, 4'-fluoro-4 [4 (2-thioxo-1 frontal bone were soldered to a miniature benzimidazolinyl) piperidino] , socket and fixed to the skull with dental possesses a potent antipsychotic activity cement. with lesser liability to an extrapyramidal The animals were allowed two weeks to action in experimental animals (1, 2). We recover from surgery and individually housed have previously shown that timiperone i n the plastic observation box (40 x 40 x 60 produced a moderate synchronization of cm) placed in the air conditioned and sound spontaneous EEG in acute experiments (3) attenuated room with dim lighting. All and that this action may be attributed to a recordings were made with an ink writing suppression of the ascending reticular electroencephalograph (San-Ei, model la activating system (4). Based on these 52). Behavior of the cats was simultaneously findings, the present study was undertaken monitored by a videocamera. to investigate the effect of timiperone on the The sleep-wakefulness cycle of the cats sleep-wakefulness cycle using cats with was measured for 6 hours (9 a.m. to 4 p.m.). chronically implanted electrodes in com The records were visually scored in 1 -min parison with that of the other buthyro epochs into the following five categories: phenone, . arousal, rest, slow wave light sleep (SWLS), Six adult cats of either sex (2.3-3.1 kg) slow wave deep sleep (SWDS) and para were used, and chronic implantation of doxical sleep (PS). After EEG recording, electrodes was performed under pentobarbital percentage of awaking (arousal+rest), SWS anesthesia (30 mg/kg, i.p.). The screw (SVVLS+SWDS) and PS time were electrode for the cortical EEG was placed calculated. over the somatosensory cortex, and the At the start of recording, the animal subcortical coaxial electrode was stereo received intraperitoneal injection of either taxically inserted into the hippocampus saline or timiperone hydrochloride (Daiichi using the brain atlas of Reinoso-Suarez (5). Seiyaku) and haloperidol hydrochloride (syn Two silver wires were implanted deeply into thetized in our institute) which were dissolved the neck muscle for EMG recording, and eye in physiological saline. In an experimental movement potential was recorded from a period of two days, the first day was taken dental screw in the left orbit. The recording for the control recording (saline), and the electrodes and the indifferent electrode in the second day was used for a recording under 392 the treatment of drug. The cats were used in the present experiments, the eTrect OT repeatedly at intervals of at least a week. The timiperone on the sleep-wakefulness cycle statistical significance of differences between was qualitatively similar to that of haloperidol. the control and treated group was analyzed This finding is in agreement with the obser by Student's t-test. At the end of each vation of Monti (8) who described an increase experiment, the stereotaxic placement of the in the SWS time and a decrease in the PS subcortical electrode was verified his time after intraperitoneal haloperidol in cats. tologically. The suppresive effect of timiperone on PS Timiperone and haloperidol at the doses was observed at a dose as low as 0.03 mg/ used did not produce appreciable changes in kg and more markedly at 0.3 mg/kg. Its the electroencephalographic pattern, but they potency was approximately 10 times higher altered the sleep-wakefulness cycle (Table 1 than that of haloperidol. and Fig. 1). Following timiperone (0.03 to On the other hand, it was shown that 0.3 mg/kg), no changes could be observed timiperone siginificantly potentiated the in the awaking time when compared to each caudate spindle evoked by electrical stimu saline treated animal. However, the PS time lation of the caudate nucleus (4). A recent was dose-dependently decreased, while the report indicates that the caudate spindle is SWS time was dose-dependently increased. enhanced by receptor antagonists There were significant changes in PS and in such as haloperidol and and that SWS after the 0.3 mg/kg dose of timiperone. these enhancing actions are completely In addition, the number of PS phases was antagonized by the dopaminergic agonist, reduced, and this reduction was in the range (9). In our previous paper (4), of 40-66% as compared with the control timiperone suppressed apomorphine and values at the highest dose. Moreover, the PS methamphetamine-induced stereotyped be latency was significantly lengthened. havior in rats more strongly than did Similarly, haloperidol (1 and 3 mg/kg) dose haloperidol, and its potency was ap dependently increased SWS time and proximately 8-10 times higher than that of decreased PS time. The increase in SWS and haloperidol. a decrease in PS were statistically significant. From these findings, it was considered It is well known that antipsychotic drugs that the central dopaminergic system might could influence the sleep mechanisms (6, 7). be partially involved in the effect of timi perone on sleep mechanisms in cats. However, according to Jouvet (10), sleep cycles are modulated by the other brain biogenic amines such as noradrenaline and serotonin. Therefore, further investigations are required with respect to the detailed mechanisms of the effect of timiperone on the sleep cycle.

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