Electrical Stimulation of the Ventral Tegmental Area Induces Reanimation from General Anesthesia

Abstract

BACKGROUND Methylphenidate or a D1 dopamine receptor agonist induce reanimation (active emergence) from general anesthesia. We tested whether electrical stimulation of dopaminergic nuclei also induces reanimation from general anesthesia. METHODS In adult rats, a bipolar insulated stainless steel electrode was placed in the ventral tegmental area (VTA, n = 5) or substantia nigra (SN, n = 5). After a minimum 7-day recovery period, the isoflurane dose sufficient to maintain loss of righting was established. Electrical stimulation was initiated and increased in intensity every 3 min to a maximum of 120μA. If stimulation restored the righting reflex, an additional experiment was performed at least 3 days later during continuous propofol anesthesia. Histological analysis was conducted to identify the location of the electrode tip. In separate experiments, stimulation was performed in the prone position during general anesthesia with isoflurane or propofol, and the electroencephalogram was recorded. RESULTS To maintain loss of righting, the dose of isoflurane was 0.9% ± 0.1 vol%, and the target plasma dose of propofol was 4.4 μg/ml ± 1.1 μg/ml (mean ± SD). In all rats with VTA electrodes, electrical stimulation induced a graded arousal response including righting that increased with current intensity. VTA stimulation induced a shift in electroencephalogram peak power from δ (<4 Hz) to θ (4–8 Hz). In all rats with SN electrodes, stimulation did not elicit an arousal response or significant electroencephalogram changes. CONCLUSIONS Electrical stimulation of the VTA, but not the SN, induces reanimation during general anesthesia with isoflurane or propofol. These results are consistent with the hypothesis that dopamine release by VTA, but not SN, neurons induces reanimation from general anesthesia.

Optogenetic activation of dopamine neurons in the ventral tegmental area induces reanimation from general anesthesia

“…Optical stimulation of VTA DA neurons in ChR2+ mice reliably restored behavioral arousal and the righting reflex during CSSGA. However, the arousal response was slower to develop compared with VTA electrical stimulation in rats (34). It is interesting to note that a similar attenuation of effect between optical and electrical stimulation was observed by others in VTA DA-mediated reward behaviors.…”

“…A variety of experimental approaches have been used to study the neural circuits that underlie anesthetic-induced unconsciousness and recovery of consciousness in rodents, including designer receptors exclusively activated by designer drugs (DREADDs) (35), genetic manipulations (36), local and systemic drug administration (10,(37)(38)(39), microdialysis (40,41), targeted brain lesions (42,43), and electrical stimulation (34). Optogenetics is a novel tool that provides distinct advantages over previous techniques used to study anesthetic-induced unconsciousness and recovery of consciousness in rodents.…”

“…Impulse train stimulation (16 pulses, 10-ms duration, 30 Hz, repeated every 2 s) was used to simulate a burst firing pattern (33), and periodic step stimulation (cycles of 5-ms pulses at 50 Hz for 60 s, followed by 30-s pauses with no stimulation) was used to simulate the electrical stimulation protocol used in our previous rat study (34). The two stimulation protocols were tested on separate days, with at least 3 d of rest provided between experiments, in random order.…”

Brainstem Stimulation Increases Functional Connectivity of Basal Forebrain-Paralimbic Network in Isoflurane-Anesthetized Rats

“…Pharmacological stimulation of the central thalamus of the AAS has been found to restore consciousness in a minimally conscious patient (Schiff et al, 2007). Likewise, experiments in animals have been successful in reversing the anesthetic state by exogenous stimulation that acts via medial thalamic, basal forebrain, and brainstem components of the AAS (Alkire et al, 2007;Chemali et al, 2012;Fenik et al, 2005;Pillay et al, 2011;Solt et al, 2014). Thus, experimental modulation of the AAS has potential to provide important insight into the regulation of the state of consciousness.…”

Dopamine in the ventral tegmental area facilitates emergence from general anesthesia

“…Electrical stimulation of the VTA, but not the substantia nigra, promoted emergence from isoflurane anesthesia (12). Dopaminergic neurons in the substantia nigra, which project to the caudate/putamen, are apparently more concerned with execution of movements (13,14) than motivating action.…”