Synaptic mechanisms of thiopental-induced alterations in synchronized cortical activity

Abstract

Background: Anesthetic depth after barbiturate administration has been correlated with distinct electroencephalogram (EEG) patterns. The current study used a rat neocortical brain slice micro-EEG preparation to investigate synaptic mechanisms underlying thiopental-induced transitions in synchronized neuronal activity. Methods: Concentration-dependent cellular actions of thiopental were investigated in brain slices using specific pharmacologic probes, whole cell patch clamps, and extracellular field recordings. θ-Like micro-EEG oscillations were elicited in neocortical slices by mimicking subcortical cholinergic and gamma-aminobutyric acid (GABA) afferent input with carbachol (100 μM), a cholinergic agonist, and bicuculline (10 μM) a GABA(A) antagonist. Results: In the presence of 20 μM thiopental, micro-EEG slowing from θ (7.3 ± 0.9 HZ, mean ± SD, n = 19) to δ frequencies (2.5 ± 0.5 Hz, n = 11) was associated with a threefold prolongation of inhibitory currents. Burst suppression activity occurred at 50 μM thiopental, and appeared to result from direct activation of GABA(A)-gated chloride currents, observed with voltage clamp recordings, and mimicked with a direct acting GABA(A) agonist, muscimol (1 μM). Isoelectric activity occurred at 100 μM thiopental, and likely resulted from reduced glutamatergic transmission, evidenced by depressed excitatory postsynaptic potentials. Glutamatergic excitation was required for burst suppression activity, because glutamate receptor antagonists blocked thiopental-induced bursts; forcing a transition to isoelectric activity. Conclusions: Thiopental produced a continuum of EEG- like states in brain slices similar to those observed in vivo. The progression of thiopental-induced effects appear to have resulted from specific cellular actions that were recruited in a concentration-dependent manner. Progressive enhancement of synaptic inhibition followed by depression of excitatory transmission led to micro-EEG frequency slowing, burst suppression, and isoelectric activity.