γ-Aminobutyric Acid–mediated Neurotransmission in the Pontine Reticular Formation Modulates Hypnosis, Immobility, and Breathing during Isoflurane Anesthesia

Abstract

Background Many general anesthetics are thought to produce a loss of wakefulness, in part, by enhancing gamma-aminobutyric acid (GABA) neurotransmission. However, GABAergic neurotransmission in the pontine reticular formation promotes wakefulness. This study tested the hypotheses that: 1) relative to wakefulness, isoflurane decreases GABA levels in the pontine reticular formation; and 2) pontine reticular formation administration of drugs that increase or decrease GABA levels increases or decreases, respectively, isoflurane induction time. Methods To test hypothesis 1, cats (n = 5) received a craniotomy and permanent electrodes for recording the electroencephalogram and electromyogram. Dialysis samples were collected from the pontine reticular formation during isoflurane anesthesia and wakefulness. GABA levels were quantified using high performance liquid chromatography. For hypothesis 2, rats (n = 10) were implanted with a guide cannula aimed for the pontine reticular formation. Each rat received microinjections of Ringer’s (vehicle control), the GABA uptake inhibitor nipecotic acid, and the GABA synthesis inhibitor 3-mercaptopropionic acid. Rats were then anesthetized with isoflurane and induction time was quantified as loss of righting reflex. Breathing rate was also measured. Results Relative to wakefulness, GABA levels were significantly decreased by isoflurane. Increased power in the electroencephalogram and decreased activity in the electromyogram caused by isoflurane co-varied with pontine reticular formation GABA levels. Nipecotic acid and 3-mercaptopropionic acid significantly increased and decreased, respectively, isoflurane induction time. Nipecotic acid also increased breathing rate. Conclusion Decreasing pontine reticular formation GABA levels comprises one mechanism by which isoflurane causes loss of consciousness, altered cortical excitability, muscular hypotonia, and decreased respiratory rate.

Hypocretin and GABA Interact in the Pontine Reticular Formation to Increase Wakefulness

“…Considered with data showing that delivering hypocretin-1 to the PnO increases GABA levels in the PnO 13 and causes inhibition of some PnO neurons, 10 and with evidence that GABAergic transmission in the PnO is wakefulness promoting, 13,[19][20][21][22][23][24][25] the present results support the interpretation that increasing GABAergic transmission in the PnO is one mechanism by which hypocretin-1 increases wakefulness. The results are discussed below relative to the functional roles of hypocretin-1 in rat PnO and the mechanisms by which hypocretin-1 administered to the PnO causes an increase in wakefulness.…”

“…14 Numerous studies have demonstrated that GABAergic transmission in the PnO increases wakefulness and inhibits REM sleep. 13,[19][20][21][22][23][24][25] The present study provides the first test of the hypothesis that the wakefulness-promoting effects of delivering hypocretin-1 into the PnO are mediated by GABA A receptors as well as by hypocretin receptors. This hypothesis was evaluated by determining whether (1) microinjection of hypocretin-1 into the PnO causes a concentration-dependent increase in wakefulness, (2) this increase in wakefulness is blocked by coadministration of the hypocretin receptor-1 (hcrt-r1) antagonist SB-334867, and (3) coadministration of the GABA A receptor antagonist bicuculline also blocks the wakefulness response to hypocretin-1.…”

“…38 GABA levels in the PnO are also greater during wakefulness than during the loss of consciousness produced by the general anesthetic isoflurane. 24 Furthermore, loss of endogenous hypocretin increases recovery time from isoflurane anesthesia. 39 The present finding that the hypocretin-1-induced increase in wakefulness was blocked by coadministration of bicuculline ( Figure 6) demonstrates that the wakefulness response is mediated by GABA A centage of time spent in REM sleep varied significantly as a function of drug treatment ( Figure 6C, F 3,24 = 6.03; P = 0.003).…”

Development of the γ-amino butyric acid (GABA)-ergic signaling system and its role in larval swimming in sea urchin

“…Given that GABAergic function in the brain is mediated mainly by GABA A Rs (Lüscher and Keller, 2004), we used bicuculline, an antagonist of GABA A R (Owens and Kriegstein, 2002;Vanini et al, 2008) to investigate this involvement further. Exposure to bicuculline inhibited the swimming activities of 1d.p.f.…”

Czy rzeczywiście znany jest efekt farmakodynamiczny środków stosowanych podczas znieczulenia ogólnego u noworodków, niemowląt i dzieci? Przegląd eksperymentalnych i klinicznych badań dotyczących działania neurodegeneracyjnego

“…They secrete acetylcholine (Ach) at the nerve ends, both during the physical activity and REM phase. The use of isoflurane and ketamine, as well as other neurotransmitters, is associated with increased amounts of GABA and reduced amounts of Ach in the reticular system [13,14].…”