Dopamine-enhancing medications to accelerate emergence from general anesthesia.

5 January 2013 D OPAMINERGIC neurotransmission is prominently implicated in emergence from the minimal conscious state,1,2 general anesthesia,3 and in sleep–wake regulation.4 The molecular mechanisms for these effects are still incompletely understood. The anatomical and neurochemical signatures of the dopamine (DA) system for arousal under conditions of general anesthesia are clinically important to understand. First, from a clinical point of view, accurate knowledge of the molecular basis for emergence from general anesthetics with agents for which no specific antagonists exists (i.e., inhalational agents) and for other anesthetic regimens could lead to the development of a range of new drugs specifically designed for rapid emergence. Such therapeutics could perhaps be useful in the future for routine anesthesia practice. For example, rapid arousal of elderly patients undergoing surgical procedures requiring general anesthesia may prove valuable for reducing cognitive dysfunction and/or early delirium postoperatively. Second, a better understanding of the neuronal mechanisms by which DA increases the emergence from anesthesia will also help in the management of patients with DA abnormalities as may be the case for patients with Parkinson disease, schizophrenic patients treated with depot neuroleptics (long-acting dopamine-2 receptor [D2R] antagonists) and drug abusers. In this issue of Anesthesiology, Taylor et al.5 report that the dopamine-1 receptor (D1R) agonist 6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide but not the D2R agonist quinpirole reduces the time to emergence from isoflurane anesthesia in rats by 85% compared with placebo. The authors conclude that selective activation of D1Rs is sufficient to induce emergence from isoflurane general anesthesia and that D2Rs are not needed.5 These new data in the setting of isoflurane anesthesia are intriguing and supplement older data reporting similar findings with phenobarbital anesthesia.6,7 Specifically, Horita et al.7 investigated the effects of a D1R agonist (1-phenyl2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol) and a D2R antagonist (raclopride) on duration of phenobarbital anesthesia in rats (administered only 20 min after induction with 40 mg/kg intraperitoneal phenobarbital to reduce pharmacokinetic effects on emergence). They documented that the D1R agonist reduced the time to emergence by approximately 30% and found that this effect could be abolished by a D1R antagonist.7 However, in contrast to the current study,5 Horita et al.7 reported that the D2R antagonist raclopride and atropine also reversed the effect of the D1R agonist. Thus, the findings of Horita et al. suggest that the arousing effects of D1R agonists require the coactivation of these two receptors (D1R and D2R). Interestingly, although nonsignificant, the study by Taylor et al.5showed decreases in the time from emergence of anesthesia in the rats treated with the D2R agonist quinpirole (from 330 to 189 s) and had their sample (n = 6) been larger, this effect may have been significant. Regardless, it is clear that the effects of the D1R agonist was stronger than that of the D2R agonist (quinpirole), which could reflect in part its effects on D2R autoreceptors that would lead to a decrease in DA release. In the previous study, Horita et al.7 also provide evidence that the dopaminergic effects (driven by D1R but presumably requiring background D2R tone) are mediated by downstream cholinergic effects (because these effects were blocked by atropine). In the context of the importance of D2Rs, Solt et al.3 reported that Dopamine-enhancing Medications to Accelerate Emergence from General Anesthesia