In this study we found that methylphenidate actively induces emergence from isoflurane anesthesia by increasing arousal. In addition, our plethysmography and blood gas experiments revealed that methylphenidate also increases minute ventilation, which increases the rate of anesthetic elimination from the brain.20
Emergence from isoflurane anesthesia is dose-dependent,21
therefore methylphenidate-induced ventilatory stimulation likely contributes to accelerating time to emergence.
Our protocol for testing loss of righting reflex did not utilize a rotating anesthetizing chamber, and the average dose of isoflurane required to maintain loss of righting in our study was 0.9%. This dose was slightly higher than the dose previously reported for loss of righting in uninstrumented mice using a rotating anesthetizing chamber (0.81% isoflurane, with a 95% confidence interval between 0.78% and 0.84%).5
The stimulation provided by the temperature probe and the IV catheter in our rats was likely comparable to the stimulation provided by the rotating anesthetizing chamber in uninstrumented mice.
Electroencephalogram and plethysmography studies were performed separately from behavioral experiments with some modifications in the experimental protocols designed to minimize motion artifacts. Electroencephalogram studies performed under very similar experimental conditions as the behavioral studies demonstrated a consistent shift from delta to theta power within 30 s of methylphenidate administration. These results agree with a previous study that found methylphenidate induces a theta rhythm in rats anesthetized with chloral hydrate.22
The plethysmography experiments performed at a higher dose of isoflurane (1.5%, or approximately 1 minimum alveolar concentration) demonstrated increases in respiratory rate and minute ventilation. It is reasonable to conclude that these changes are similar to the changes that would have been observed in animals that regained the righting reflex in the behavioral studies.
Cholinergic arousal pathways have been studied most extensively in the context of emergence from general anesthesia. Hudetz and colleagues3
showed that intraventricular administration of the cholinesterase inhibitor neostigmine to rats during isoflurane anesthesia produced an increase in cross-approximate entropy of the electroencephalogram, and elicited behavioral signs of arousal such as spontaneous limb movements and orofacial explorative movements. Alkire and colleagues4
showed that injection of nicotine into the central medial thalamus induced return of righting during continuous inhalation of sevoflurane, providing evidence for cholinergic pathways that activate the thalamus inducing arousal from general anesthesia. In patients, physostigmine has been reported to reduce postoperative somnolence after halothane general anesthesia.23
In studies involving human volunteers, physostigmine reversed propofol-induced loss of consciousness in 9 of 11 subjects,24
and reversed sevoflurane-induced loss of consciousness in 5 of 8 subjects.25
Both of these studies reported that administration of physostigmine produced significant increases in auditory steady-state response and bispectral index, which are neurophysiological correlates of increased arousal.
Orexinergic arousal pathways have also been shown to play an important role in emergence from general anesthesia. Orexins are arousal-promoting peptide neurotransmitters released by neurons in the perifornical area of the hypothalamus, and abnormal orexinergic signaling leads to narcolepsy.26,27
Mesa and colleagues28
reported that a patient suffering from narcolepsy underwent three different operations between 1979 and 1995, and required 8-10 h to emerge from general anesthesia each time. Kelz and colleagues5
demonstrated in mice that both genetic and pharmacologic ablation of orexinergic signaling delays time to righting after discontinuation of isoflurane or sevoflurane general anesthesia. Interestingly, the inhaled anesthetic concentration required to produce loss of righting was unchanged in orexin-ablated mice compared to wild-type, indicating that orexinergic neurons are not involved in the mechanisms underlying induction of general anesthesia. In a separate study by Zecharia et al.
intraventricular administration of orexin-A was shown to reduce time to righting after propofol and dexmedetomidine administration.
Although there are several monoaminergic arousal pathways, they have been less well studied in the context of emergence from general anesthesia. Luo and Leung6
recently reported that injection of histamine into the basal forebrain of rats decreased time to righting after isoflurane general anesthesia, increased respiratory rate, and shifted electroencephalogram activity from a burst suppression pattern (“deep” general anesthesia) to a delta pattern (“lighter” general anesthesia). Their results suggest that enhanced histaminergic neurotransmission in the basal forebrain may also play a role in emergence from general anesthesia.
Decades ago, the clinical utility of methylphenidate as an analeptic, i.e.
, a central nervous system stimulant, was explored in psychiatry and anesthesiology.30
However, at that time, its mechanism of action was unknown. Psychiatrists reported using the drug to promote arousal in patients suffering from overdoses of antipsychotic medications,31
and to facilitate psychiatric interviewing.32
Studies conducted in the perioperative period suggested that methylphenidate promoted faster recovery after general anesthesia.33,34
However, the only placebo-controlled, double-blinded study reported no difference in recovery time.35
Prior to the United States Food and Drug Administration's black box warning on droperidol in 2001, the drug was widely used in anesthesiology practices as a sedative and antiemetic. Our present findings suggest that the widespread use of droperidol may have confounded the results of some of the earlier clinical studies of methylphenidate. On the other hand, because methylphenidate is now widely prescribed to treat attention deficit hyperactivity disorder, there are recent reports of increased anesthetic requirements in patients who take methylphenidate.36,37
These reports are consistent with our finding that methylphenidate antagonizes isoflurane anesthesia.
Methylphenidate is known to inhibit dopamine and norepinephrine transporters with similar affinities (Ki
= 250 nM and 150 nM, respectively).7
Dopaminergic neurons in the ventral tegmental area and substantia nigra pars compacta promote arousal, and play an important role in cognition and reward through projections to the thalamus, basal forebrain, nucleus accumbens, cortex, lateral dorsal tegmentum, and locus ceruleus.38
A third cluster of wake-active, dopaminergic neurons has been recently identified in the ventral periaqueductal gray area.39
There is recent evidence that enhancement of dopaminergic neurotransmission increases ventilatory drive in cats,40-42
which suggests that a dopaminergic mechanism may also play a role in the methylphenidate-induced increase in alveolar ventilation.
Noradrenergic neurons in the locus ceruleus promote arousal through projections to the thalamus, basal forebrain, preoptic areas, and cortex,2
and their inhibition is important in the sedative actions of propofol43
In addition, arousal-promoting histaminergic neurons arising from the tuberomammillary nucleus may also play a role in the actions of methylphenidate,8
although the mechanisms underlying this pathway have yet to be clearly defined. Therefore methylphenidate likely induces emergence by enhancing arousal-promoting monoaminergic (i.e.
, dopaminergic, noradrenergic, and possibly histaminergic) neurotransmission.
We found that administration of droperidol inhibits both the arousal-promoting effects and the increase in alveolar ventilation induced by methylphenidate during isoflurane general anesthesia. It has been reported that 3 mg/kg of droperidol has no effect on isoflurane potency in rats,45
and that the EC50
for loss of righting in mice is 40 mg/kg,46
suggesting that our relatively modest rodent dose of 0.5 mg/kg had little impact on the anesthetic state of the animals in our study. This conjecture is further supported by the lack of electroencephalogram changes observed in our animals after droperidol administration. Droperidol is known primarily as an antagonist at D2 dopamine receptors, but it has also been shown to inhibit α1 adrenergic receptors.47,48
Therefore our results with droperidol are consistent with the notion that dopaminergic and noradrenergic neurotransmission play important roles in methylphenidate-induced emergence. Further studies will be necessary to elucidate which arousal pathways are responsible for the specific actions of methylphenidate, although it is likely that the simultaneous activation of multiple monoaminergic arousal pathways contributes to its efficacy.
Because the molecular mechanisms underlying the actions of general anesthetics are poorly understood, it has not been possible to design antagonists of general anesthetics. However, our results suggest that methylphenidate actively induces emergence from isoflurane anesthesia by stimulating monoaminergic arousal pathways. These results demonstrate a novel approach for identifying clinically useful antagonists of general anesthetics at the level of neural circuits. Methylphenidate has a well-established safety record in children and adults, through its more than two decades of use in the treatment of Attention Deficit Hyperactivity Disorder.7
Our findings suggest that intravenous methylphenidate could be used in adult and pediatric patients at the conclusion of surgery to reverse general anesthetic-induced unconsciousness and aid in the recovery of cognitive function.