Epileptogenic drugs in a model nervous system: Electrophysiological effects and incorporation into a phospholipid layer

Mechanisms of epileptiform activity in a model nervous system (buccal ganglia of Helix pomatia) are presented. The ganglia contain the identified giant neurons B1 through B4. For epileptiform activity, pentylenetetrazol (1 mmol/L to 40 mmol/L) or etomidate (12.5 μmol/L to 500 μmol/L) were applied. Membrane pressure was measured using a Wilhelmy film balance. In electrophysiological experiments, both drugs induced several effects in all studied neurons: membrane resistance increased, down-stroke of action potentials declined, and all types of chemical synaptic potentials decreased (the latter concerns pentylenetetrazol only). The threshold was 1 mmol/L of pentylenetetrazol and 12.5 μmol/L of etomidate. Epileptiform potentials developed in neurons that had expressed the membrane mechanisms underlying pacemaker potentials. The threshold of this development was again 1 mmol/L of pentylenetetrazol and 12.5 μmol/L of etomidate. Epileptiform depolarizations appeared with 40 mmol/L of pentylenetetrazol and 500 μmol/L of etomidate. In biochemical experiments, both drugs incorporated into an artificial phospholipids membrane and increased pressure in the membrane. The threshold of pressure increase was 1 mmol/L of pentylenetetrazol and 12.5 μmol/L of etomidate. Pressure increased dose-dependently and was 69% and 63% above starting pressure of 10 mN/m with epileptogenic concentrations of pentylenetetrazol (40 mmol/L) and of etomidate (500 μmol/L), respectively. It is postulated that amphiphilic substances incorporate into cell membranes and increase intramembranous pressure, and that this disturbs several membrane processes mechanically and leads to epileptic depolarizations in pacemaker neurons.