EFFECTS OF VOLATILE ANESTHETICS ON THE KINETICS OF INHIBITORY POSTSYNAPTIC CURRENTS IN CULTURED RAT HIPPOCAMPAL-NEURONS

1. The effects of the volatile anesthetics enflurane, halothane, and i soflurane on gamma-aminobutyric acid (GABA) receptor-mediated inhibito ry postsynaptic currents (IPSCs) were studied in cultured rat hippocam pal neurons. The experimental concentrations of anesthetics were measu red directly using gas chromatography. All three anesthetics increased the overall duration of IPSCs, measured as the time to half-decay (T1 /2). Clinically effective concentrations of anesthetics [between 0.5 a nd 1.5 times MAC (minimum alveolar concentration)] produced between 10 0 and 400% increases in T1/2. These effects were fully reversible, and did not involve alterations in the reversal potential for the IPSC (E (IPSC)). 2. The decay of the IPSC was fitted as a sum of two exponenti al functions, yielding a fast component (T(fast) = 20 ms), and a slow component (tau(slow) = 77 ms), such that the fast component accounted for 79% of the IPSC amplitude and 52% of the total charge transfer. Al l three anesthetics produced concentration-related increases in the am plitude and charge transfer of the slow component, while simultaneousl y decreasing the amplitude and charge transfer of the fast component. Thus T1/2 approximated tau(fast) under control conditions, but approxi mated tau(slow) in the presence of the anesthetics. 3. Varying the cal cium chelating agents in the recording pipettes had no effect on the q uality or magnitude of alterations in IPSC kinetics produced by haloth ane, suggesting that variations in intracellular calcium levels are no t required for the effect of halothane on the time course of the IPSC. 4. The (+)-stereoisomer of isoflurane produced greater increases in t he duration of the IPSC than the (-)-isomer when applied at approximat ely equal concentrations, suggesting that there is a structurally sele ctive site of interaction for isoflurane that modulates the GABA(A) re ceptor. 5. These results suggest that the previously shown abilities o f volatile anesthetics to potentiate responses to exogenously applied GABA and to prolong the duration of GABA-mediated synaptic inhibition may be due to an alteration in the gating kinetics of the GABA(A) rece ptor/channel complex. Prolongation of synaptic inhibition in the CNS i s consistent with the physiological effects that accompany anesthesia and may contribute to the mechanism of anesthetic action.