Effects of ketamine and propofol on muscarinic plateau potentials in rat neocortical pyramidal cells

Abstract

Propofol and ketamine are widely used general anaesthetics, but have different effects on consciousness: propofol gives a deeply unconscious state, with little or no dream reports, whereas vivid dreams are often reported after ketamine anaesthesia. Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, while propofol is a {gamma}-aminobutyric-acid (GABAA) agonist, but these mechanisms do not fully explain how these drugs alter consciousness. Most previous in vitro studies of cellular mechanisms of anaesthetics have used brain slices or neurons in a nearly "comatose" state, because no "arousing" neuromodulators were added. Here we tested mechanisms of anaesthetics in slices after adding the cholinergic agonist muscarine to partly mimic an "awake-like" state. Using whole-cell patch-clamp recordings from layer 2/3 pyramidal cells (L2/3PCs) in rat medial prefrontal cortex (mPFC) slices, we saw that muscarine induced long-lasting depolarizing plateau potentials (PPs) and spiking following brief depolarizing current injections. According to leading theories of consciousness and working memory, L2/3PCs and PPs are particularly important for these cognitive functions. After 2 hours of pre-incubation with ketamine or propofol, the muscarine-induced PPs were altered in different ways: 3 {micro}M propofol reduced the PPs and (significantly) spiking, whereas 20 {micro}M ketamine seemed to enhance PPs and spiking (non-significantly). Brief wash-in of these drug concentrations failed to induce such effects, probably due to insufficient equilibration by diffusion in the slices. In contrast, pre-incubation with 100 {micro}M ketamine suppressed the PPs and spiking. The different effects on PPs may be related to contrasting clinical effects: ketamine causing atypical anaesthesia with vivid, "psychedelic" dreaming while propofol causes less dreaming. However, high ketamine or propofol concentrations both suppressed PPs, suggesting possible connections between PPs, desynchronized activity, and consciousness. More experiments are needed to test these tentative conclusions.