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.

Long-term potentiation (LTP) at the basal-dendritic synapses of CA1 pyramidal cells was induced by a single 200 Hz stimulation train (0.5-1 sec duration) in freely behaving rats during one of four behavioral states: awake-immobility (IMM), walking, slow-wave sleep (SWS), and rapid eye movement sleep (REM). Field EPSPs generated by basal-dendritic excitation of CA1 were recorded before and up to 1 d after the tetanus. After a tetanus during any behavioral state, basal-dendritic LTP was >170% of the baseline for the first hour after the tetanus and decayed to approximately 120% 1 d after. LTP induced during walking was significantly larger than that induced during IMM, SWS, or REM, which had similar LTP magnitudes. To test the hypothesis that septohippocampal cholinergic activity enhanced LTP during walking as compared with IMM, rats were either pretreated with muscarinic cholinergic antagonist scopolamine or injected with IgG192-saporin in the medial septum to selectively lesion cholinergic septohippocampal neurons. Pretreatment with scopolamine decreased the LTP induced during walking but did not affect that induced during IMM, such that the difference between the LTP induced during walking and IMM was abolished after scopolamine. Rats injected with IgG192-saporin showed no difference in the LTP induced during walking and IMM, and scopolamine did not reduce the LTP during walking. In contrast, sham-lesion rats showed larger LTP induced during walking than IMM, and the LTP induced during walking was attenuated by scopolamine. This is the first demonstration of an enhancement of hippocampal LTP by physiologically activated cholinergic inputs.

1. We recorded the extracellular excitatory postsynaptic potentials (EPSPs) in CA1 in the freely behaving rats after stimulation of the apical dendritic and basal dendritic afferents. The apical dendritic population EPSP was negative at the apical dendritic layers and positive at stratum oriens and alveus. The basal dendritic population EPSP was negative at basal dendritic layer (stratum oriens) and positive at the cell body and apical dendritic layers. 2. We delivered various tetanic stimulus patterns in an attempt to elicit long-term potentiation (LTP) at the apical dendritic synapse of CA1 pyramidal cells. A 200-Hz high-frequency train (HF) 1 s in duration was more successful than theta-frequency primed bursts (PBs; 1 or 4 priming pulses followed by 10 or 4 pulses at 100 Hz) in eliciting LTP of the apical dendritic population EPSP, recorded either ipsilaterally or contralaterally. 3. Tetanus applied to the apical dendritic afferents occasionally elicited long-term depression (LTD) at an intensity lower than the LTP threshold. LTD persisted to > or = 1 day after a tetanus. 4. High-intensity tetanic stimulations often elicited hippocampal afterdischarges (ADs). If the AD duration was brief (< 15 s), apical dendritic LTP could follow the AD. However, if the AD duration was long, no apical dendritic LTP was observed. Tetanus that evoked an apical dendritic LTP typically evoked a short hippocampal AD < 15 s in duration. 5. LTP of the basal dendritic population EPSP was readily elicited either after an HF or a PB tetanus of low (1.5-2 times threshold) stimulus intensity.(ABSTRACT TRUNCATED AT 250 WORDS)

The participation of ionotropic glutamatergic synapses in the generation of hippocampal electroencephalography (EEG) of behaving rats has not been systematically studied. In this study, field potentials in hippocampal CA1 were recorded following injection of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, or vehicle control, either into the lateral ventricles or directly into the hippocampus or the medial septum. Intraventricular (i.c.v.) AMPA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX, 5-10 microg) decreased the commissural evoked potential and the amplitude of the hippocampal EEG, including the theta rhythm. Theta frequency was decreased by 10 microg, but not 5 microg DNQX i.c.v. Unilateral intrahippocampal injection of DNQX (5 microg) only decreased the amplitude, but not the frequency, of the theta rhythm near the site of injection, without affecting theta amplitude or frequency at the opposite hippocampus. Other than theta, the large irregular activity (with a delta frequency peak at 1-2 Hz) and gamma EEG (30-100 Hz) were also decreased by i.c.v. and intrahippocampal injections of DNQX. Intrahippocampal injection of NMDA receptor antagonist D-2-amino-5-phosphonovaleric acid (D-APV, 2.5 microg) decreased the amplitude of the theta rhythm and, less consistently, the gamma EEG. The frequency of the theta rhythm and the peak of the commissural evoked potential were not significantly affected by intrahippocampal D-APV injection. Medial septal injections of D-APV or D,L-APV (2.24 microg in 0.4 microl), but not DNQX (10 microg in 0.4 microl), decreased the amplitude of the hippocampal theta significantly, but theta frequency was not significantly affected. It is concluded that both NMDA and AMPA receptors in the hippocampus are involved in generating the amplitude of the hippocampal EEG of theta and gamma frequencies, while NMDA receptors in the medial septum are involved in controlling the amplitude of theta and gamma EEG in the hippocampus. Excitatory glutamatergic synaptic currents, activated by afferents from the entorhinal cortex and CA3, are suggested to participate in hippocampal EEG activities.

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The participation of GABA(B) receptors in hippocampal EEG generation was studied by intracerebroventricular (icv) and intracerebral infusions of GABA(B) receptor antagonist p-(3-aminopropyl)-p-diethoxymethyl-phosphinic acid (CGP35348) in freely behaving rats. During awake-immobility, icv CGP35348 induced a theta rhythm and increased gamma waves (30-100 Hz) in the hippocampus. The immobility theta peaked at 6-7 Hz and had a theta phase in CA1 stratum radiatum of approximately 160 degrees with reference to the theta at the alveus, when compared with approximately 130 degrees during walking. Immobility theta power peaks at 6-7 Hz was also found in normal rats, and it was detected in 27% of the EEG segments during immobility. Incidence of immobility theta increased to 87.5% after 480 nmol of CGP35348 icv. Muscarinic antagonist scopolamine (5 mg/kg, ip) suppressed the induction of immobility theta and the gamma power increase after icv CGP35348. CGP35348 icv did not significantly change the hippocampal theta power at 7-8 Hz during walking (theta fundamental), but it increased power at 12-15 Hz, at the second harmonic of theta. CGP35348 icv also increased 30-50 Hz gamma power during walking. Medial septal infusion of CGP35348 (12 nmol in 0.4 microl) increased the power and the frequency of the hippocampal theta second harmonic during walking, but did not increase gamma activity. Infusion of CGP35348 (8 nmol in 0.4 microl) in the hippocampus increased the local gamma activity at 30-100 Hz, but did not induce immobility theta or affect the walking theta rhythm. In conclusion, icv GABA(B) receptor blockade increased an atropine-sensitive input that generated an immobility theta rhythm, while GABA(B) receptor blockade of the medial septum increased atropine-resistant theta harmonics possibly generated by apical dendritic spikes. GABA(B) receptor blockade may enhance cognitive task performance by activating hippocampal theta and gamma rhythms in behaving rats.

Summary:Purpose: To determine whether hippocampal afterdischarges (ADs) and excitability changes were induced by γ -aminobutyric acid (GABA) B -receptor blockade in adult, freely moving rats.Methods: A specific GABA B -receptor antagonist CGP35348, CGP55845A, or CGP55699A was injected intracerebroventricularly (i.c.v.), and EEGs and behaviors of rats were analyzed.Results: CGP35348 (56-110 µg, i.c.v.) induced afterdischarges (ADs) ∼60% of the time, starting at the hippocampus or neocortex. Neocortical-onset ADs began with sporadic discharges and were <3 mV. Hippocampal-onset ADs were bilateral, >5 mV, and spread to the entorhinal cortex and amygdala, often ending in a rebound AD and accompanied with stereotypic jumping, forelimb clonus, and wet-dog shakes. The CGP35348-induced hippocampal AD had an onset frequency (5-9 Hz) that was higher than the electrically evoked AD (2-4 Hz). CGP35348 i.c.v. also increased the mean starting frequency of an electrically evoked hippocampal AD from 3.6 Hz to 5.3 Hz. Hippocampal gamma activity (25-80 Hz) increased up to twofold for 30 min after a hippocampal but not a neocortical AD. A single dose of CGP35348 induced repeated ADs of increasing duration. Pairedpulse inhibition of the evoked potentials in CA1, at interpulse interval of <100 ms, was decreased after but not before a hippocampal AD. CGP56999A (i.c.v.) gave results similar to those with CGP35348, whereas CGP55845A (i.c.v.) rarely induced ADs.Conclusions: GABA B -receptor blockade increases seizure susceptibility by reducing AD threshold and increasing the frequency and spread of a hippocampal AD. Hippocampal excitability (based on paired-pulse test) and gamma activity increased after but not before a hippocampal AD. Key Words: CGP35348-Gamma waves-Theta rhythmKindling-Paired-pulse depression.γ -Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the cerebral cortex, and it mediates inhibition through GABA A and GABA B receptors. GABA Areceptor functions are relatively well understood. Suppression of GABA A -receptor function induces seizures (1,2), whereas GABA A -receptor agonists are effective anticonvulsants. In contrast, the participation of GABA B receptors in partial (focal) seizure generation is not well established.Despite their effectiveness against generalized absence seizures (3,4), GABA B -receptor antagonists were found to induce convulsive, presumably partial seizures in rats (5-7). GABA B -receptor antagonists also induced epileptiform activity in vitro (8,9), and one type of GABA Breceptor polymorphism has been associated with tempo- ral lobe epilepsy in humans (10). The GABA B -receptor R1 knockout mice was reported to manifest spontaneous generalized seizures (11,12), but the origin of the seizures was not clear. In studies that induced seizures by GABA Breceptor antagonists, EEG was not used in seizure detection except in one study (5).We are interested in the conditions in which GABA Breceptor blockade may lead to seizures. Although the functions of several types of GABA B receptors...

The performance of rats that were partially kindled in the hippocampus was assessed on an 8-arm radial arm maze with 4 baited arms. In rats first trained and then kindled, deficits were found on a place task in which rats reached the goal arms of the maze using salient extramaze spatial cues, but not on an intramaze cue task in which rats reached the goal arms using salient intramaze cues. Acquisition of a new place task on the maze was not different between kindled and control rats. In conclusion, partial hippocampal kindling disrupted the retention but not the acquisition of a spatial or place task; retention of a nonspatial cue task was not disrupted.