Propofol Facilitates Glutamatergic Transmission to Neurons of the Ventrolateral Preoptic Nucleus

Abstract

Background There is much evidence that the sedative component of anesthesia is mediated by γ-aminobutyric acid A receptors on hypothalamic neurons responsible for arousal, notably in the tuberomammillary nucleus. These γ-aminobutyric acid A receptors are targeted by GABAergic neurons in the ventrolateral preoptic area (VLPO): when these neurons become active, they inhibit the arousal-producing nuclei and induce sleep. According to recent studies, propofol induces sedation by enhancing VLPO-induced synaptic inhibition, making the target cells more responsive to γ-aminobutyric acid A. We explored the possibility that propofol also promotes sedation less directly by facilitating excitatory inputs to the VLPO GABAergic neurons. Methods Spontaneous excitatory postsynaptic currents were recorded from VLPO cells – principally mechanically isolated, but also in slices from rats. Results In isolated VLPO GABAergic neurons, propofol increased the frequency of glutamatergic spontaneous excitatory postsynaptic currents without affecting their mean amplitude. Propofol’s action was mimicked by muscimol and prevented by gabazine, respectively a specific agonist and antagonist at γ-aminobutyric acid type-A receptors. It was also suppressed by bumetanide, a blocker of Na+-K+-Cl− cotransporter-mediated inward Cl− transport. In slices, propofol also increased the frequency of spontaneous excitatory postsynaptic currents and, at low doses, accelerated firing of VLPO cells. Conclusion Propofol induces sedation, at least in part, by increasing firing of GABAergic neurons in ventrolateral preoptic area, indirectly by activation of γ-aminobutyric acid type-A receptors on glutamatergic afferents: because these axons/terminals have a relatively high internal Cl− concentration, they are depolarized by GABAergic agents such as propofol which thus enhance glutamate release.

Distinctive Recruitment of Endogenous Sleep-promoting Neurons by Volatile Anesthetics and a Nonimmobilizer

“…Though the finding of increased c-Fos-immunoreactivity in GABAergic VLPO neurons is congruent with volatile anesthetic-induced activation of sleep-promoting VLPO neurons suggested by previous single label c-Fos expression studies in vivo and by electrophysiological recordings in hypothalamic slices, 18-22 important discrepancies exist. Previous work showed an increase in the absolute number of c-Fos-immunoreactive cells in the VLPO after in vivo isoflurane and halothane exposure, and a significant induction of c-Fos in VLPO following exposure to a subhypnotic dose of isoflurane 22 not reproduced herein.…”

“…17,44,50,53,54 Studies across phyla as distinct as invertebrates and mammals have demonstrated that anesthetic drugs are capable of activating endogenous sleep-promoting neural systems. 18-22,55,56 Hence, we believe that exploring the commonalities and recognizing the key differences in the genesis of these states will be critical to advance our understanding both of anesthetic mechanisms as well as sleep neurobiology.…”

“…Indeed, exposure to supra-hypnotic doses of a variety of general anesthetics including barbiturates, propofol, dexmedetomidine, chloral hydrate, isoflurane, and halothane all induce c-Fos expression in putative sleep-promoting VLPO neurons. 18-22 While activation of the VLPO could be indirect, arising via disinhibition, the volatile anesthetic isoflurane directly depolarizes the subset of VLPO neurons that are electrophysiologically indistinguishable from those involved in the genesis and maintenance of natural sleep. 22 Evidence regarding the MnPO's role in anesthetic-induced hypnosis is less clear.…”

Ethanol‐Induced Loss‐of‐Righting Response During Ethanol Withdrawal in Male and Female Rats: Associations with Alterations in Arc Labeling

“…Both GABA and glutamate have been shown to modulate sleep ⁄ wakefulness in the preoptic area (Chou et al, 2003;Gallopin et al, 2000;Stenberg, 2007;Takahashi et al, 2009). Pharmacological manipulation of preoptic area neurons by sedatives such as propofol promotes sleep, whereas activation of glutamatergic neurons in this area promotes wakefulness (Li et al, 2009;Stenberg, 2007;Tung et al, 2001). Therefore, increased Arc density in the preoptic area could contribute to the reduced sleep time seen in EW animals.…”

What is unconsciousness in a fly or a worm? A review of general anesthesia in different animal models

“…Rats with bilateral lesions of the TMN require less isoflurane to induce LORR (Luo & Leung, 2011). In rodent models, general anesthetics such as propofol and isoflurane can increase the inhibitory drive of these VLPO neurons onto the TMN (Luo & Leung, 2011;Nelson et al, 2002), and this could be facilitated by increased excitatory transmission to VLPO by glutamatergic afferents (Li, Guan, Krnjevic, & Ye, 2009). Injection of GABA A agonists onto the TMN inhibits wakefulness (Lin, Sakai, Vanni-Mercier, & Jouvet, 1989).…”