Disruption of synchronous gamma oscillations in the rat hippocampal slice: A common mechanism of anaesthetic drug action

Abstract

1 At the molecular level much progress has been made towards elucidating the mechanisms of action of general and dissociative anaesthetics. However, little is known about how these molecular actions may lead to disruption of cognitive function. 2 A promising physiological correlate of cognitive function is the ability of spatially separate areas of the brain to synchronize firing patterns via mutual inhibitory, gamma‐frequency (20–80 Hz) electrical oscillations. Here we examine the effects of five different anaesthetic/hypnotic agents with different primary mechanisms of action on these oscillations in the hippocampus. 3 Gamma oscillations were elicited simultaneously at two sites at either end of area CA1 by tetanic stimulation. Such oscillations are synchronous between these areas even when separated by up to c. 4 mm in control conditions. 4 Agents which act directly on GABA_A receptor‐mediated inhibition had different effects on synchronous gamma oscillations. Thiopental (10–200 μm) markedly disrupted the oscillation and resulting synchrony whereas the benzodiazepines diazepam and temazepam (0.05–1.0 μM) had little effect. 5 The opiate morphine (10–200 μM) and dissociative agent ketamine (10–100 μM) had a different profile of effects on gamma oscillations. However, as with thiopental, both agents markedly disrupted between site synchrony. These three agents demonstrated this effect at aqueous concentrations relevant to anaesthetic ED₅₀. 6 Using the hippocampus as a model neuronal network we propose that, despite differing primary mechanisms of action, anaesthetics may disrupt cognitive function by interfering with the mechanism of generation of synchronous firing patterns between spatially separate areas of the brain. British Journal of Pharmacology (1998) 125, 483–492; doi:10.1038/sj.bjp.0702113