5-HT2A receptor-mediated excitation on cerebellar fastigial nucleus neurons and promotion of motor behaviors in rats.

It has long been known that serotonergic afferent inputs are the third largest afferent population in the cerebellum after mossy fibers and climbing fibers. However, the role of serotonergic inputs in cerebellar-mediated motor behaviors is still largely unknown. Here, we show that only 5-HT2A receptors among the 5-HT2 receptor subfamily are expressed and localized in the rat cerebellar fastigial nucleus (FN), one of the ultimate outputs of the spinocerebellum precisely regulating trunk and limb movements. Remarkably, selective activation of 5-HT2A receptors evokes a postsynaptic excitatory effect on FN neurons in a concentration-dependent manner in vitro, which is in accord with the 5-HT-elicited excitation on the same tested neurons. Furthermore, selective 5-HT2A receptor antagonist M100907 concentration-dependently blocks the excitatory effects of 5-HT and TCB-2, a 5-HT2A receptor agonist, on FN neurons. Consequently, microinjection of 5-HT into bilateral FNs significantly promotes rat motor performances on accelerating rota-rod and balance beam and narrows stride width rather than stride length in locomotion gait. All these motor behavioral effects are highly consistent with those of selective activation of 5-HT2A receptors in FNs, and blockage of the component of 5-HT2A receptor-mediated endogenous serotonergic inputs in FNs markedly attenuates these motor performances. All these results demonstrate that postsynaptic 5-HT2A receptors greatly contribute to the 5-HT-mediated excitatory effect on cerebellar FN neurons and promotion of the FN-related motor behaviors, suggesting that serotonergic afferent inputs may actively participate in cerebellar motor control through their direct modulation on the final output of the spinocerebellum.

Histamine excites neurons of the inferior vestibular nucleus in rats by activation of H1 and H2 receptors.

By using brain slice preparations and extracellular recordings, the effect of histamine on spontaneous firing activities of neurons in the inferior vestibular nucleus (IVN), a key structure responsible for integration of vestibular, multisensory, and cerebellar inputs, in rats was investigated. Perfusing slices with histamine (1-10µM) elicited an excitatory response on IVN neurons. The responses were not blocked by low Ca(2+)/high Mg(2+) medium, indicating a direct postsynaptic effect of the amine. Furthermore, the histamine-induced excitation was partially blocked by selective histamine H1 receptor antagonist mepyramine (1µM) and H2 receptor antagonist ranitidine (1µM), respectively. Co-application of mepyramine and ranitidine nearly totally antagonized the histamine-induced excitation. Additionally, both selective H1 receptor agonist 2-pyridylethylamine (30-300µM) and H2 receptor agonist dimaprit (10-100µM) effectively mimicked the excitatory action of histamine on IVN neurons. Moreover, selective H4 antagonist JNJ7777120 (10µM) and agonist VUF8430 (30-300µM) had no effect on IVN neurons. These results demonstrate that histamine excites IVN neurons via postsynaptic H1 and H2 rather than H4 receptors, and suggest that the central histaminergic system actively modulate all four major vestibular nuclei including the IVN and may subsequently influence the vestibular nuclei-related reflexes and functions.

Histamine promotes rat motor performances by activation of H(2) receptors in the cerebellar fastigial nucleus.

The cerebellar fastigial nucleus (FN), together with the interpositus nucleus (IN), constitutes the two final output nuclei of the spinocerebellum and plays an important role in body and limb movements. Previous studies have revealed a direct histaminergic projection from the hypothalamus to the cerebellar nuclei and an excitatory effect of histamine on the IN neurons. However, role of hypothalamic histaminergic projection in the FN has been still little known. Here we show that histamine elicited the FN neurons of rats a concentration-dependent excitatory response in vitro. The histamine-induced excitation on FN neurons was mediated by postsynaptic histamine H2 rather than H1 receptors. In behavioral tests, microinjection of histamine into bilateral FNs remarkably improved motor performances of rats on both accelerating rota-rod and balance beam. Selective H2 receptor antagonist ranitidine considerably declined those motor performances and selective H2 receptor agonist dimaprit mimicked the facilitation effect of histamine on the movements. But selective H1 receptor antagonist triprolidine and agonist 2-pyridylethylamine had no effect. Furthermore, microinjection of histamine into bilateral FNs narrowed stride width of footprint but did not influence wire suspension, whereas microinjection of histamine into bilateral INs increased stride length and promoted suspension. These results demonstrate that histamine enhances rat motor balance and coordination through modulation of both proximal and distal muscles by activation of histamine H2 receptors in the cerebellar FN and IN, and suggest that the hypothalamocerebellar histaminergic projections may modulate the final outputs of the spinocerebellum and participate in the cerebellum-mediated motor control.

A role for orexin in central vestibular motor control.

The absence of orexin results in narcolepsy-cataplexy. While the function of the central orexinergic system in sleep regulation has been well studied, the role of orexin in motor control is largely unknown. Here, we show that orexin-A acts via OX(1) and OX(2) receptors to directly depolarize neurons in the rat lateral vestibular nucleus (LVN), a subcortical motor center, and enhance their sensitivity. A dual ionic mechanism involving both Na+-Ca²+ exchangers and inward rectifier K+ channels underlies these effects. Furthermore, orexin-A regulates central vestibular-mediated posture, motor balance and negative geotaxis. Orexin is critical when an animal is facing a major motor challenge as opposed to during rest and general movements. Therefore, orexin participates not only in sleep and emotion (nonsomatic) but also in motor (somatic) regulation, suggesting that the central orexinergic system plays an important role in somatic-nonsomatic integration. These findings may account for why the absence of orexin results in narcolepsy-cataplexy.