The combined effects of halothane and lamotrigine on excitatory postsynaptic potentials and use-dependent block in the rat dentate gyrus in vitro

Halothane affects synaptic transmission in the rat hippocampus with a 50% e ffective dose (ED50)orrelating with clinical figures for minimum alveolar a nesthetic concentration (MAC). Halothane dose-dependently suppresses glutam ate receptor-mediated excitatory postsynaptic potentials (EPSPs) in the rat hippocampus. It also inhibits voltage-gated Na+ channels. The anticonvulsa nt lamotrigine acts as a Na+ channel antagonist and inhibits glutamate rele ase after Na+ channel activation. Given their known similar sites of action , the combination of halothane and lamotrigine may alter the inhibition pro duced by either drug alone. Extracellular recordings of field EPSPs were ob tained from the dentate gyrus in the presence of 100 mu M picrotoxin (to bl ock GABA, receptors). Stimulation at 30 Hz (200 ms, pulse duration 0.1 ms, six pulses) allowed us to investigate use-dependent block (UDB). Once a sta ble equilibrium was established, halothane and lamotrigine were administere d via the perfusate, and recordings were collected. Both halothane (n = 12) and lamotrigine (n = 6) exhibited reversible inhibition of the EPSP (ED50 0.28 mM [1.2%] and 100 mu M, respectively) at low-frequency stimulation. Sl ices (n = 6) exposed to halothane 0.2 mM (0.75%), then to lamotrigine, show ed reduced sensitivity compared with lamotrigine alone. Halothane 0.2 mM po tentiated the control UDB (Pulse 6: 31% +/- 11% control versus 20.5% +/- 2. 5% halothane 0.75%; P < 0.05; n = 6). Lamotrigine had no effect on control UDB. The combination(n = 6) did not alter UDB effects compared with control s or lamotrigine alone. Halothane may reduce the effect of lamotrigine on g lutamate release, either at the receptor or via effects at the inactivated Na+ channel. The site of interaction requires further examination. Implicat ions: The general and local anesthetic drugs halothane and lamotrigine act at both the glutamate receptor and the Na+ channels and, in our experiments , independently inhibited synaptic transmission at low-frequency stimulatio n. Although halothane potentiated control use-dependent block, lamotrigine had no effect. Halothane attenuated the inhibitory dose-dependent effects o f lamotrigine on synaptic transmission at a low frequency. The clinical imp ortance of this interaction in patients presenting for anesthesia remains u nanswered.