Fig. 5. Schematic illustrating mechanisms of action of isoflurane, 3-mercaptopropionic acid (3-MPA), and nipecotic acid (NPA) within the pontine reticular formation. (  A ) During wakefulness, pontine reticular formation γ-aminobutyric acid (GABA;  red dots ) is released from vesicles contained in presynaptic terminals, increasing chloride ion (Cl^–) conductance by activation of postsynaptic and extrasynaptic GABA^Areceptors. GABA is then actively removed from the synaptic cleft by uptake mechanisms (GABA transporters). (  B ) Isoflurane decreases pontine reticular formation GABA levels, in part, by inhibiting action potential dependent neurotransmitter release,  62,by potentiation of GABA^Areceptor–mediated inhibition of GABAergic neurons,  15,and/or by presynaptic inhibition (disfacilitation) of excitatory inputs acting on GABAergic neurons.  35,These three actions of isoflurane on GABAergic transmission likely occur in combinations that vary as a function of brain region. (  C ) Inhibition of glutamic acid decarboxylase (GAD) by 3-MPA decreases GABA levels in the pontine reticular formation, decreases arousal, and facilitates isoflurane-induced loss of wakefulness. (  D ) Inhibition of pontine reticular formation GABA uptake mechanisms by NPA increases GABA levels, increases arousal, and prolongs isoflurane induction time.  A –D include extrasynaptic GABA receptors because these receptors are targets for anesthetic drugs  61,and because GABA measured by  in vivo microdialysis is thought to act at these extrasynaptic receptors .33