Quinine, an alkaloid derived from the bark of the chichona tree, is used clinically in the treatment of malaria and as an anti-spasmodic drug. Quinine has been shown to significantly attenuate extracellular potassium transients in vitro (Smirnov et al. 1999) and in vivo (Zetterstrom et al. 1995). The mechanism of this reduction is unknown. Extracellular potassium transients are a ubiquitous feature of epileptic seizure activity and have been suggested to facilitate ictal bursting (Fertziger & Ranck, 1970). We therefore investigated the anti-convulsant effects of quinine on spontaneous ictal epileptiform activity in vitro. Furthermore, we characterized the effect of quinine on CA1 pyramidal cell intrinsic properties to elucidate the mechanism of potassium transient suppression.

Hippocampal slices (0.4 mm) were prepared from Sprague-Dawley rats (anaesthetised with 7.4 mg kg^-1 ketamine/0.7 mg kg^-1 medetomidine I.P., humanely killed by cervical dislocation) and kept in an interface chamber. Spontaneous non-synaptic epileptiform activity was induced in the CA1 region by exposing hippocampal slices to low-Ca²⁺ ACSF (Jefferys & Haas, 1982).

Application of 200 µM quinine significantly reduced low-Ca²⁺ burst amplitude and duration and increased burst frequency after ~20 min (n = 9). Quinine blocked low-Ca²⁺ ictal activity after ~60 min. Suppression was partially reversible after > 60 min wash. The peak antidromic evoked population spike amplitude was not significantly affected (n = 3). After 60 min in 200 µM quinine, CA1 pyramidal cell resting membrane potential, input resistance, and action potential threshold (from both current injection and antidromic stimulation) were not significantly affected (n = 5). In response to a 200 ms depolarizing pulse, quinine slightly attenuated the size of the first action potential (83 ± 8 % control, mean ± S.D., P < 0.01, Student’s t test, n = 5) and increased its width (148 ± 32 % control, P < 0.05, n = 5). The second action potential amplitude was significantly depressed (56 ± 25 % control for 1.0 nA pulse, P < 0.05, n = 5) and dramatically widened (1758 ± 1581 % control for 1.0 nA pulse, n = 5). The modulation of the second action potential, but not of the first one (amplitude 58 ± 21 % control, width 2126 ± 169 % control for a 2 nA pulse, n = 3), increased with increased current injections.

These results suggest that the suppression of ictal epileptiform activity and extracellular potassium transients by quinine is due, at least in part, to a limitation of the maximum firing rate of cells. Furthermore, this modulation is independent of synaptic function.This work was supported by the MRC.

Fertziger, A.P. & Ranck, J.B. (1970). Exp. Neurol. 26, 571-585.

Jefferys, J.G.R. & Haas, H.L. (1982). Nature 300, 448-450.

Smirnov, S., Paalasmaa, P., Uusisaari, M., Voipio, J. & Kaila, K. (1999). J. Neurosci. 19, 9252-9260.

Zetterstrom, T.S., Vaughan-Jones, R.D. & Grahame-Smith, D.G. (1995). Neurosci. 67, 815-821.