The Septohippocampal System Participates in General Anesthesia

Abstract

How the brain mediates general anesthesia is not known. We report that two interconnected structures in the forebrain, the medial septum and the hippocampus, participate in maintaining awareness and movements during general anesthesia. In the awake, freely behaving rat, inactivation of the medial septum or the hippocampus by local injection of a GABA(A) receptor agonist, muscimol, decreased the dose of a general anesthetic needed to induce a loss of the tail-pinch response or a loss of righting reflex. Septohippocampal inactivation also suppressed the behavioral hyperactivity or the delirium stage associated with general anesthesia. An increase and decrease of 30-50 Hz (gamma) waves in the hippocampus correlated with an increase and decrease in behavioral activity, respectively. Similar results were found for both volatile (halothane and isoflurane) and nonvolatile (propofol and pentobarbital) anesthetics. We conclude that the behavioral hyperactivity induced by a general anesthetic is mediated in part by the septohippocampal system, and that depression of the septohippocampal system increases the potency of a general anesthetic. It is suggested that more potent general anesthetics or adjuvants may be developed by maximizing the pharmacological depression of the septohippocampal system.

The hippocampus participates in a pharmacological rat model of absence seizures

“…However, at a fixed time after GBL injection, the peak frequency of PDs was lower after muscimol as compared to saline pre-infusion into the hippocampus, suggesting that neural activity of the hippocampus contributes to general maintenance of PDs of a specific frequency. We reported a similar effect that hippocampal inactivation enhanced the loss of righting response, decreased gamma power, and increased <2 Hz power in the hippocampal and neocortical LFPs in response to a general anesthetic (Ma et al, 2002). GBL is known to have hypnotic effects (Guidotti and Ballotti, 1970), also suggested by its effect in decreasing PD peak frequency, increasing < 2-Hz power and decreasing gamma power in the LFPs (Supplementary Fig.…”

“…Eight rats were implanted with 23-gauge stainless steel guide cannulae bilaterally into the hippocampus (Ma et al, 2002) at P4.6, L2.5, V3.0 ( Supplementary Fig. 1B).…”

“…Immediately following infusion, GBL was injected at 200 mg/ml i.p., and LFPs (from hippocampal and thalamic electrodes bilaterally, and right frontal cortex) were recorded continuously for at least 30 min. Based on ~1 mm radius spread from the center of infusion (Martin, 1991, Ma et al, 2002, it was estimated that ~30% of the dorsal hippocampus, and little of the ventral hippocampus, was affected by bilateral injection of muscimol. Each rat was given both saline and muscimol infusion, in experiments separated by at least 7 days, randomly starting with saline or muscimol first.…”

Lesion of cholinergic neurons in nucleus basalis enhances response to general anesthetics

“…Three general anesthetics -halothane, sodium pentobarbital and propofol -were used, following procedures used in previous studies (Ma et al, 2002;Ma and Leung, 2006;Long et al, 2009). Halothane (2%) in pure oxygen was delivered by a calibrated vaporizer, at 8 l/min, into a Plexiglas observation chamber (30 × 30 × 30 cm), and leaked through small holes at the top.…”

“…As a measurement of the delirium, also known as stage II anesthesia, induced by a volatile anesthetic (Guedel, 1951), horizontal movements (locomotion) were quantified by measuring the number of infrared beam interruptions after administration of halothane (Ma et al, 2002;Long et al, 2009). Each lesioned or control rat was habituated for 25 min in the chamber before the delivery of halothane (2%).…”