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  • To examine the possible role of mGluRs

    2021-09-23

    To examine the possible role of mGluRs in the LH/PFA in the hypercapnic ventilatory response, a nonspecific antagonist of mGluRs, MCPG, was microinjected into the LH/PFA. MCPG elicited a significantly increased hypercapnic ventilatory response in awake rats, but not during sleep, in the light and dark phases, suggesting that glutamate, acting on mGluRs in the LH/PFA, exerts an inhibitory modulation of the central chemoreflex, and that this function may be dependent on the sleep-wake cycle. The glutamatergic metabotropic receptors are divided into three groups: Group I, consisting of mGluR1 and mGluR5; Group II, consisting of mGluR2 and mGluR3; and Group III, comprising of mGluR4, mGluR6, mGluR7 and mGluR8. Group I mGluRs are coupled to Gq and stimulate the phospholipase C pathway. Conversely, Group II and group III mGluRs are coupled to Gi, which prevents the formation of cyclic adenosine 3′5′-monophosphate (cAMP) (Conn and Pin, 1997). Group II and III mGluRs are expressed both presynaptically and postsynaptically but they predominate in presynaptic elements, where their activation can decrease glutamate and other neurotransmitters transmitter release (Anwyl, 1999; Cartmell and Schoepp, 2000). In the LH/PFA, the predominant location of group II mGluR has not been described but group III mGluRs are believed to be localized primarily in presynaptic terminals in this area. It has been suggested, according to data from whole-cell voltage- and current-clamp recording in mouse hypothalamic slices, that group III mGluRs are probably located on both glutamate and GABA presynaptic Tasquinimod that innervate the hypocretin neurons. I was demonstrated that the activation of group III mGluRs resulted in a reduction of synaptic activity recorded in hypocretin neurons by a presynaptic mechanism which envolved the selective inhibition of glutamate release, but not of GABA, mediated by group III mGluRs (Acuna-goycolea et al., 2004). Since the receptors of Groups II and III are of inhibitory action (Blumcke et al., 1996), we raised the possibility that, when injected into the LH/PFA, the effect of MCPG on the hypercapnic ventilatory response could be due to the blockade of metabotropic receptors of Groups II and III. To test this hypothesis, we performed, in another experimental group, the microinjection of a selective antagonist for Group II/III mGluRs, LY341495. With the microinjection of LY341495, we observed a large increase in the ventilatory response to CO2 during wakefulness, but not during sleep, both in the light phase and in the dark phase, suggesting that the inhibitory modulation of the central chemoreflex exerted by glutamatergic neurotransmission in the LH/PFA possibly involves the Group II/III mGluRs. Although the effects of MCPG and LY341495 were observed both in the light period and in the dark period, a greater effect occurred in the light period. In the dark period, microinjection of MCPG increased the hypercapnic ventilatory response by 29%, whereas in the light period, the increase was 39%. LY341495, on the other hand, increased the ventilatory response to CO2 in the dark period by 44%, and in the light period, by 57%. In view of such results, it is reasonable to assume that glutamatergic inhibitory modulation in the LH/PFA may occur through the activation of Group II/III mGluRs expressed on orexinergic neurons, which have a recognized chemosensitive function (Li and Nattie, 2010; Williams et al., 2007). A higher inhibition during the light period is consistent with the lower activity of the orexinergic neurons in this phase of the diurnal cycle (Desarnaud et al., 2004), and with the lower chemosensitive activity of this region in the light period (Dias et al., 2010; Li et al., 2013). The inhibition of the hypercapnic chemoreflex exerted by mGluRs might have a regulatory role, providing a negative feedback of the central chemoreflex. The fact that this effect was observed only during wakefulness may be related to the state-dependent control of central chemoreception. Moreover, it is well known that during sleep, the respiratory system is particularly susceptible to instability due to, among other factors, the absence of two important stimuli for breathing: the voluntary control and the effect of alertness, the so-called “wakefulness drive to breathe” (Krimsky and Leiter, 2005). Thus, some negative feedback mechanisms of the central chemoreflex probably operate just during wakefulness. If these mechanisms acted during sleep in the same way as during wakefulness, the instability of breathing control would be even greater, which could increase the incidence of sleep-related respiratory disease.