Activation of D1 dopamine receptors induces emergence from isoflurane general anesthesia

Abstract

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.

Fig. 1

The D1 receptor agonist chloro-APB decreases time to emergence from isoflurane anesthesia. (A) Rats inhaled isoflurane (1.5%) and received normal saline, chloro-APB (3 mg/kg IV), or the D2 receptor agonist quinpirole (5 mg/kg IV) after 40 min (solid arrow). Five minutes later, the animals were removed from the anesthetizing chamber (dashed arrow). Time to emergence was defined as the time from termination of isoflurane to return of righting (i.e., all four paws touching the floor). (B) Scatter plot of time to emergence for rats that received normal saline, chloro-APB and quinpirole (n = 6 each). The lines represent the medians. ** p < 0.01.

Fig. 2

Chloro-APB induces emergence during continuous isoflurane general anesthesia. (A) Rats inhaled isoflurane at a dose sufficient to maintain loss of righting for a total of 40 min, and received normal saline or the D1 receptor antagonist SCH-23390. Five minutes later, chloro-APB or quinpirole was administered IV. Isoflurane was continued at the same dose until return of righting occurred or 30 min elapsed. (B) For each drug regimen, the percentage of rats that had restoration of righting within 30 min of dopamine agonist administration is shown (n = 6 each). Normal saline alone elicited no arousal response. Rats that received normal saline followed by chloro-APB exhibited restoration of righting in a dose-dependent manner. Pretreatment with the D1 receptor antagonist SCH-23390 (0.2 mg/kg IV) instead of normal saline inhibited restoration of righting by the highest dose of chloro-APB (3 mg/kg IV). Rats that received normal saline followed by the D2 receptor agonist quinpirole did not exhibit restoration of righting. *** Posterior probability greater than 0.99.

Fig. 3

Spectral analysis of electroencephalogram data reveals a decrease in δ power induced by chloro-APB that is inhibited by SCH-23390. Warm colors (e.g., red) represent higher power at a given frequency, while cool colors (e.g., blue) represent lower power. (A) A representative spectrogram computed from a rat in the awake state shows predominance of θ power (4–8 Hz). (B) A representative spectrogram computed from a rat inhaling isoflurane (1.0%) shows predominance of δ power (<4 Hz) before and after administration of normal saline. However, administration of chloro-APB (3 mg/kg IV) promptly induced a decrease in δ power. (C) A representative spectrogram computed from a rat that received the D1 receptor antagonist SCH-23390 (0.2 mg/kg IV) instead of normal saline shows that similar to the rat in (B), δ power is dominant during inhalation of isoflurane (1.0%), before and after administration of SCH-23390. However, after the administration of SCH-23390, chloro-APB (3 mg/kg IV) failed to induce a decrease in δ power. (D) A representative spectrogram computed from a rat that received normal saline followed by the D2 receptor agonist quinpirole (5 mg/kg IV) shows that quinpirole did not induce a decrease in δ power.

Fig. 4

Electroencephalogram power spectra computed for each of 4 animals during continuous isoflurane general anesthesia. (A) The 2-min windows used to compute power spectra before dopamine agonist administration (blue, “PRE”), and after administration (red, “POST”). (B) Power spectra computed from animals that received normal saline prior to chloro-APB, showing results of the Kolmogorov-Smirnov test for the 2-min periods before and after chloro-APB administration. At a 0.05 significance level (with Bonferonni correction) the Kolmogorov-Smirnov test rejects the null hypothesis at all frequencies except those marked with white squares. Statistically significant decreases in power occurred at most frequencies under 15 Hz. (C) Power spectra computed from animals that received the D1 receptor antagonist SCH-23390 (0.2 mg/kg IV) prior to chloro-APB (3 mg/kg IV). After SCH-23390, chloro-APB failed to induce statistically significant changes in the power spectrum. (D) Power spectra computed from animals that received normal saline followed by quinpirole (5 mg/kg IV). Quinpirole induced no statistically significant changes in the power spectrum.