Effects of the H3-receptor agonist, imetit on the mouse cortical EEG and sleep-wake cycle and ciproxifan-induced waking

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From this and other studies, it is clearly established that H₃R-antagonists promote waking and improve vigilance. An important corollary question is whether H₃R-agonists induce or facilitate sleep. It was also important to verify if the waking effect of H₃R-antagonists could be reversed by H₃R-agonists. To this aim, the effects of imetit (a potent and selective H₃R-agonist) were examined in the same mouse model (n=8) during lights-off phase, when the animals spent most of the time awake at baseline (defined as the waking period).

When administered alone before lights-off, imetit (1, 3 or 10 mg/kg i.p.) decreased cortical fast rhythms and markedly increased the power spectral density of the neocortical slow activity (d + q ranges, mainly 0.8-5 Hz, Figure 3) and spindles (8-15 Hz, not shown), resulting in a state of high voltage electrical activity (Figure 3). The effects on the cortical EEG were manifested on a 4h polygraphic recording as an increase in slow wave sleep and decrease in wake duration. Paradoxical sleep decreased slightly at all doses without reaching statistical significance (Figures 3, 5). Such effects were detectable at a dose of 1 mg/kg (although insignificant over the 4h analyzed period) and increased at 3 and 10 mg/kg (Figures 3, 5). The data are consistent with those obtained in the cat using a-methylhistamine, a chiral H₃R-agonist [20]. These effects of imetit in the mouse were similar to those seen with BP2-94, another H₃-receptor agonist that in the cat induced a dramatic increase in the power spectral density of cortical slow activity, associated with a significant increase in slow wave sleep [4], a phenomenon similar to that seen during the recovery phase from sleep deprivation. H₃-receptor agonists might therefore have beneficial effects, helping the brain to recover from fatigue, mental exhaustion or sleep deprivation due to diverse causes. They might also be potentially superior to the classical antihistamines, the H₁-receptor antagonists and other classes of hypnotics that induce slow wave sleep associated with prominent paradoxical sleep reduction, incompatible with physiological sleep, as their effect on paradoxical sleep might not occur or could be less prominent. Clinically suitable H₃R-agonists might thus be expected to improve qualitative and quantitative aspects of sleep in some types of insomnia, e.g., those resulting from anxiety, stress or neuropathology.

The arousal effects of ciproxifan (3 mg/kg, i.p.) observed during the sleep period were dose-dependently antagonized by the H₃-receptor agonist, imetit (1, 3 and 10 mg/kg, i.p. n =8; Figures 4, 5) with a significant reduction of induced-waking occurring after 3 mg/kg imetit with wake and slow wave sleep duration returning to near control at 10 mg/kg dosing. Paradoxical sleep however, remained decreased after imetit treatment (Figure 4). The delayed latency to slow wave sleep due to ciproxifan was reversed at 10 mg/kg whereas latency to paradoxical sleep was unchanged after all imetit doses (Figure 4). These data are consistent with those from cats showing an antagonism of the waking effect of thioperamide by a-methylhistamine [20] supporting the concept of an H₃ receptor-dependent mechanism for their effects on EEG and sleep-wake parameters. However, it remains to be understood why imetit and other H₃R-agonists do not increase paradoxical sleep, as they do slow wave sleep, since a possible paradoxical sleep-permissive role of histamine neurons has been hypothesized in the mouse. This is based on a paradoxical sleep-off discharge pattern of HA-containing cells [14], on the one hand; and on the other hand, an increase in paradoxical sleep seen with acute or chronic suppression of histidine decarboxylase (HDC) using either the HDC inhibitor, a-fluoromethylhistidine or HDC KO mice [16]. In addition, both imetit and ciproxifan caused a slight decrease in paradoxical sleep (Figure 5), making it possible that targets other than H₃-receptors or HA transmission may be involved or reflecting the inverse agonist profiles of these two compounds. Additional experiments are therefore necessary.