Mefloquine increases input resistance (R_in). R_in (as % control) is plotted as a function of mefloquine perfusion duration. Cells bathed in normal ACSF before mefloquine (n = 10) are plotted separately from those bathed in ACSF containing kynurenic acid (2.0–2.4 mM; n = 5). Note larger increase in R_in for the kynurenic acid group.

Effect of various analogs of quinine on Cx50 channels. (A) Chemical structures of mefloquine and quinine. (B) Bar graph summarizing effect of chloroquine (1 mM), amodiaquine (100 μM), quinacrine (1 mM), pamaquine (1 mM), quinidine (stereoisomer of quinine, 300 μM), quinine (300 μM), and mefloquine (100 μM) on Cx50 junctional conductance (g_j) in N2A cells. Each bar represents the mean of four to six cell pairs for each treatment.

Mefloquine reduces junctional currents from N2A cells expressing Cx36, Cx50, and Cx43 in a concentration-dependent and connexin-selective manner. (A) Mefloquine decreased I_j of Cx36 in a concentration-dependent but irreversible manner. Recordings in A are from two separate cell pairs. (B) Cx50 channels were almost completely blocked by 3 μMmefloquine. (C) Higher concentration was required to elicit closure of Cx43 channels. (D) Concentration dependence of mefloquine on Cx36 (○) and Cx50 (•). Each point represents the mean of four to ten cell pairs. Each cell pair was exposed to only a single concentration. (E) Effect of 10 and 30 μMmefloquine on Cx26, Cx32, Cx36, Cx43, Cx46, and Cx50. Each bar represents the mean of four to six cell pairs.

Mefloquine reduces coupling between interneurons in rat neocortical slices. (A) Effect of mefloquine on electrical coupling between a pair of FS interneurons. Test current steps (–400 pA) were applied to cell 2. Illustrated traces are average voltage responses from 15 sequential steps. (B) Time course of coupling during perfusion of mefloquine (MFQ) or of normal ACSF (the mefloquine pair is the same as in A). Voltage responses in the injected cell and in the electrically coupled cell were measured to estimate the coupling coefficient (ΔV_{coupled cell}/ΔV_{injected cell}). Coupling was blocked by mefloquine but not significantly changed during long-lasting recordings in the absence of the drug. (C) Group data showing concentration dependence of mefloquine. Magnitude of block was quantified after ≈1 h in the absence and presence of mefloquine. Each bar represents the mean (n = 4 pairs, 3 pairs, 5 pairs, and 1 pair for control ACSF, 10 μM, 25 μM, and 50 μMmefloquine, respectively).

Effect of mefloquine on spiking in interneurons of rat neocortex. (A) Representative spike trains from control and 25 μMmefloquine conditions for an FS cell. The trains are matched for initial spike rate. Three main effects of mefloquine on spiking are illustrated. First, notice the slight decrease in spike amplitude across the train for the mefloquine condition but not the control. Second, note the increase in spike frequency adaptation in mefloquine, such that the later intervals in the train become longer. Third, although a characteristic delay occurs in spiking after the initial depolarization during the control period (see arrow), no such delay occurs in mefloquine. Drug-induced reductions in delays before onset of spiking occurred in 6 of 9 FS cells that showed delays in the control condition. (B) Group effects of mefloquine on three spike parameters for early and late spikes in trains (mean % control, n = 14 cells). Spike width and AHP amplitude were not affected, nor was height of the first spike in trains. A modest but significant decrease in height occurred for spikes late within trains (15th spike; P < 0.05, mefloquine vs. control, paired t test). (C) Group results on spike frequency adaptation. Spike frequency for each interspike interval is plotted as fraction of the frequency during the initial interval; thus, values >1.0 indicate increased frequency compared with the first interval, whereas values <1 indicate decreased frequencies. Note that frequencies increase during the train in control conditions but decrease in mefloquine. Differences between the two conditions are significant for all intervals after the second (P < 0.05, n = 11 FS cells).

Effect of mefloquine on spontaneous and evoked chemical synaptic transmission. (A) Spontaneous activity recorded from FS interneuron before and 61 min after exposure to 25 μM mefloquine. Spontaneous activity was clearly increased by mefloquine. An additional 20–30 min of application of TTX (1 μM) did not reduce spontaneous activity in this or four other FS cells subjected to TTX. In this group, spontaneous synaptic event frequencies went from 44.2 ± 13.6 Hz during baseline, to 91.8 ± 18.1 Hz in mefloquine, and 104.6 ± 17.3 Hz after 20–30 min of TTX. Event amplitudes were 0.50 ± 0.03 mV, 0.64 ± 0.05 mV, and 0.64 ± 0.05 mV for the baseline, mefloquine, and TTX conditions, respectively. (B) Another FS cell recorded during blockade of ionotropic glutamate receptors by kynurenic acid (2.4 mM). Note blockade of spontaneous synaptic activity in both control and mefloquine conditions. (C) Effect of mefloquine on fEPSPs recorded from the CA1 area of the hippocampus. Effects were determined for 10 μM (for 60 min; n = 3), 30 μM (for 50 min; n = 3), and 100 μM (for 30 min; n = 4) in different slices. Reduction of evoked activity was observed only at the highest concentration of the drug. Sample traces measured in control (“1”) and after application of 30 μM(“2”) and 100 μM (“3”) mefloquine are superimposed. Note the lack of obvious change in short-term facilitation. (Bottom) Group effects on fEPSPs. (D) Mefloquine did not affect IPSPs measured from somatosensory cortex. Sample traces taken before (“1”) and 80 min after 25 μMmefloquine (“2”) are superimposed. Each record is average of 20 traces. The presynaptic cell (an FS interneuron) was injected with short depolarizing steps (5 msec) to induce four action potentials at 40 Hz (one train every 12 sec). The postsynaptic cell (a low-threshold spiking interneuron) was continuously injected with depolarizing current to hold the steady-state membrane potential at about –50 mV, revealing IPSPs as negative deflections. Note that no obvious change occurs in either response amplitude or short-term depression. (Bottom) Bar graph showing group effects on IPSPs (n = 4 for 25 μM, n = 2 for 50 μM).