5-Hydroxytryptamine 6 (5-HT6) receptors are involved in learning and memory processes and are discussed as promising targets for the treatment of cognitive impairment in central nervous system ...disorders. A number of 5-HT6 antagonists are currently in the clinical development for schizophrenia and Alzheimer's disease (AD). There is some discrepancy regarding cognitive efficacy in subjects, and only limited data are available on the role of the 5-HT6 receptor in animal models of psychosis. The aim of this study was to investigate the efficacy of the selective 5-HT6 antagonists, Ro-4368554 (1-10 mg/kg, intraperitoneally) and SB-258585 (3-30 mg/kg, intraperitoneally), in animal models for schizophrenia and AD. Both compounds showed cognition-enhancing effects in object recognition, whereas only SB-258585 was able to prevent the scopolamine-induced deficit in the Morris water-maze test. Neither Ro-4368554 nor SB-258585 prevented scopolamine-induced impairment in contextual fear conditioning. Similarly, both compounds were ineffective on MK-801-induced deficits in contextual fear conditioning and spatial working memory. Ro-4368554, but not SB-258585 reversed the apomorphine-induced deficit in prepulse inhibition. Amphetamine-induced hyperlocomotion was not affected by either compound. Taken together, the overall efficacy of Ro-4368554 and SB-258585 in animal models for AD and schizophrenia is rather limited. These data show moderate efficacy in some models for AD but do not support the therapeutic potential of 5-HT6 antagonists for schizophrenia.
Abstract Serum amyloid P component (SAP)-induced neuronal apoptosis has been demonstrated on the primary culture of embryonic rat cerebral cortex in vitro . Here we present pieces of evidence that ...cell death is also induced by serum amyloid P component in living rat brain similarly to that in cell culture. Intrahippocampally administered SAP diffuses from the site of injection to the cortical and subcortical area of the rat brain and enters the cells of brain tissue in 1 week. It induces elevation of the number of in situ TdT-mediated dUTP-X nick end-labeled nuclei in the hippocampus, cortex and subcortical structures of rat central nervous system. DNA fragmentation, which is detected by the end labeling reaction, is characteristic to apoptosis. It develops in 4 weeks following exposure. Apoptosis is an important form of cell death in different neurodegenerative diseases including Alzheimer's disease. Our present work reveals that apoptosis can be induced by SAP beyond other hitherto known apoptosis inducing components of neurodegeneration. Hereby SAP seems to be an important component of the process, which leads to expanded neuronal loss in the pathomechanism of neurodegenerative diseases.
The effects of varying degrees of hypoxia on sleep-wake organization were studied in rats prepared for chronic electrophysiological recording. The influence of Piracetam (75, 50, and 500 mg/kg, i.p.) ...and Hydergine (0.5, 1, and 3 mg/kg, i.p.) on sleep-wake organization in 10.5% oxygen was also investigated. The sleep-wake organization of rats under the effect of 15.5% oxygen content was unchanged, compared to that of normoxic control. More extreme hypoxia (12.6 and 10.5% oxygen) produced dramatic changes in sleep organization without influencing gross behavior. Paradoxical sleep (PS) stages became less frequent and shortened and were totally absent in 10.5% oxygen. Frequent wakings caused disturbed and superficial sleep. Central biochemical mechanisms, peripheral chemoreceptor reflex pathways and, as a consequence, decrease of duration of deep sleep periods, may contribute to the development of hypoxic sleep disturbances. Piracetam alleviated and Hydergine moderately reversed the hypoxic sleep disturbance.
A comparative dose-response investigation of thyrotropin-releasing hormone (TRH) and L-6-ketopiperidine-2-carbonyl-leucyl-L-proline-amide (RGH-2202) was carried out on rats and cats. RGH-2202 reduced ...the occurrence of photically evoked after-discharge in rats more significantly than TRH. Neither of the two compounds influenced the parameters of visually evoked potentials. Both compounds desynchronized the background electrocortical activity in rats. The amplitude of the acoustic startle reflex in rats was decreased dose-dependently only by RGH-2202, and this effect was nearly 3 times more potent than that of TRH. Both compounds increased the time spent awake, the latency to light sleep and the proportion of light sleep in a dose-dependent manner. The higher doses of TRH equalled the effects of the lower doses of RGH-2202. In cats the latency increasing effect of TRH on paradoxical sleep was about 30% less than that of RGH-2202; furthermore, the relative increase in the proportion of light sleep coupled with a corresponding decrease of deep sleep and paradoxical sleep was significant only in the case of RGH-2202. In a complex conditioned reflex situation in cats, the dose-dependent motivation decreasing effect on food intake and, as a consequence, on spontaneous motor activity was more pronounced in the case of TRH. The effective doses of RGH-2202 and TRH in rats were nearly equal, while in cats RGH-2202 showed about 1/10 of the potency of TRH. This finding suggests a considerably lower species variability of the effects of RGH-2202.
Mannitol, a non-absorbent compound may suppress free drinking in rats. It was suggested that the osmotic accumulation of water in the intestine produced a satiety signal by distending the wall of the ...gut, which resulted in the reduction of intake. However, we never obtained this suppression during the first exposure to mannitol in water deprived rats, while subsequent administration of this compound significantly reduced the amount of the consumed fluid. Moreover, mannitol preloaded intragastrically increased and not decreased fluid intake. Results show that in water-deprived rats the accumulation of the fluid in the intestine did not result in satiety. The subsequent reduction of the fluid intake might be associated with the development of a taste aversion in the rats.
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