Activation of D1 Dopamine Receptors Induces Emergence from Isoflurane General Anesthesia

Professor of Computational Neuroscience, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts
Anesthesiology (Impact Factor: 5.88). 12/2012; 118(1). DOI: 10.1097/ALN.0b013e318278c896
Source: PubMed


Background: A recent study showed that methylphenidate induces emergence from isoflurane anesthesia. Methylphenidate inhibits dopamine and norepinephrine reuptake transporters. The objective of this study was to test the hypothesis that selective dopamine receptor activation induces emergence from isoflurane anesthesia.
Methods: In adult rats, we tested the effects of chloro-APB (D1 agonist) and quinpirole (D2 agonist) on time to emergence from isoflurane general anesthesia. We then performed a dose–response study to test for chloro-APB–induced restoration of righting during continuous isoflurane anesthesia. SCH-23390 (D1 antagonist) was used to confirm that the effects induced by chloro-APB are specifically mediated by D1 receptors. In a separate group of animals, spectral analysis was performed on surface electroencephalogram recordings to assess neurophysiologic changes induced by chloro-APB and quinpirole during isoflurane general anesthesia.
Results: Chloro-APB decreased median time to emergence from 330 to 50 s. The median difference in time to emergence between the saline control group (n = 6) and the chloro-APB group (n = 6) was 222 s (95% CI: 77–534 s, Mann–Whitney test). This difference was statistically significant (P = 0.0082). During continuous isoflurane anesthesia, chloro-APB dose-dependently restored righting (n = 6) and decreased electroencephalogram δ power (n = 4). These effects were inhibited by pretreatment with SCH-23390. Quinpirole did not restore righting (n = 6) and had no significant effect on the electroencephalogram (n = 4) during continuous isoflurane anesthesia.
Conclusions: Activation of D1 receptors by chloro-APB decreases time to emergence from isoflurane anesthesia and produces behavioral and neurophysiologic evidence of arousal during continuous isoflurane anesthesia. These findings suggest that selective activation of a D1 receptor–mediated arousal mechanism is sufficient to induce emergence from isoflurane general anesthesia.

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Available from: Ken Solt, Jul 02, 2015
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    • "In the present experiment, we estimated a recovery time of 5 min based on our observations of the time it took animals to walk normally in the recording chamber following the removal of 1% isoflurane anesthesia. Recently, a median recovery time of 330 s has been reported when animals were placed under 1.5% isoflurane for 40 min (Taylor et al., 2013). Therefore, we cannot rule out that some of the anesthesia evoked effects may have had a longer lasting influence on the electrophysiological characteristics of EP neurons. "
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    ABSTRACT: The EntoPeduncular nucleus (EP), which is homologous to the internal segment of the Globus Pallidus (GPi) in primates, is one of the two basal ganglia (BG) output nuclei. Despite their importance in cortico-BG information processing, EP neurons have rarely been investigated in rats and there is no available electrophysiological characterization of EP neurons in vivo. We recorded and analyzed the activity of EP neurons in freely moving as well as anesthetized rats, and compared their activity patterns. Examination of neuronal firing statistics during wakefulness suggested that similar to neurons recorded in the primate GPi, EP neurons are a single population characterized by Poisson-like firing. Under isoflurane anesthesia the firing rate of EP neurons decreased substantially and their coefficient of variation and relative duration of quiescence periods increased. Investigation of the relationship between firing rate and depth of anesthesia revealed two distinct neuronal groups: one that decreased its firing rate with the increase in anesthesia level, and a second group where the firing rate was independent of anesthesia level. Post-hoc examination of the firing properties of the two groups showed that they were statistically distinct. These results may thus help reconcile in vitro studies in rats and primates which have reported two distinct neuronal populations, and in vivo studies in behaving primates indicating one homogeneous population. Our data support the existence of two distinct neuronal populations in the rat EP that can be distinguished by their characteristic firing response to anesthesia.
    Frontiers in Systems Neuroscience 02/2014; 8:7. DOI:10.3389/fnsys.2014.00007
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    • "However, whether this resistance was due to primary NMDA receptor dysfunction or whether it was caused by secondary monoaminergic hyperfunction occurring as a result of the GluN2A knockout remained unclear. Such a clarification was necessary because: (i) psychostimulant drugs that facilitate the activity of dopamine and serotonin in the brain (a situation similar to that occurring in GluN2A knockouts) can increase wakefulness; (ii) drugs like amphetamines and dopamine agonists can produce analeptic effects to shorten the duration of LORR induced by general anesthetics (Chemali et al., 2012; Horita and Carino, 1991; Horita et al., 1994; Solt et al., 2011; Taylor et al., 2013). As suspected, after pretreatment with monoaminergic antagonists, knockout mice became indistinguishable from wild-type controls in their susceptibility to nitrous oxide (Petrenko et al., 2013), thereby confirming the secondary origin of the diminished hypnotic effect of this anesthetic in GluN2A knockouts (Figure 1). "
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    ABSTRACT: N-methyl-D-aspartate (NMDA) receptors are important in mediating excitatory neurotransmission in the nervous system. They are preferentially inhibited by some general anesthetics and have, therefore, been implied in the mediation of their effects. This review summarizes the main research findings available related to NMDA receptors and their role in anesthesia. The contribution of NMDA receptors to the anesthetized state is discussed separately for each of its components: amnesia, analgesia, unconsciousness and immobility. Anesthetic-induced unconsciousness and immobility have received the most attention in the research community and are the main focus of this review. In the overall perspective, however, studies using pharmacological or electrophysiological approaches have failed to reach definitive conclusions regarding the contribution of NMDA receptors to these anesthetic endpoints. None of the studies have specifically addressed the role of NMDA receptors in the amnestic effect of general anesthetics, and the few available data are (at best) only indirect. NMDA receptor antagonism by general anesthetics may have a preventive anti-hyperalgesic effect. The only and most extensively used genetic tool to examine the role of NMDA receptors in anesthesia is global knockout of the GluN2A subunit of the NMDA receptor. These animals are resistant to many intravenous and inhalational anesthetics, but the interpretation of their phenotype is hindered by the secondary changes occurring in these animals after GluN2A knockout, which are themselves capable of altering anesthetic sensitivity. Generation of more sophisticated conditional knockout models targeting NMDA receptors is required to finally define their role in the mechanisms of anesthesia.
    European journal of pharmacology 12/2013; 723(1). DOI:10.1016/j.ejphar.2013.11.039 · 2.53 Impact Factor
  • Anesthesiology 11/2012; 118(1). DOI:10.1097/ALN.0b013e318278c8cd · 5.88 Impact Factor
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