Changes in voltage‐operated calcium channels modify ethanol withdrawal hyperexcitability in mouse hippocampal slices

Abstract

SUMMARYMeasurements of hippocampal excitability were made from area CAl of isolated mouse hippocampal slices, prepared after chronic ethanol treatment in vivo, and the effects of the stereoisomers of the dihydropyridine Bay K 8644, that act at calcium channels, were investigated. The decrease in the threshold stimulation required to produce a single population spike, the leftward shift in the population spike input-output curves, and the increase in population spike amplitude, that were seen during ethanol withdrawal, were all increased by the (-) isomer of Bay K 8644. This isomer has been shown to increase opening of calcium channels. These effects of ethanol withdrawal were decreased by the (+) isomer of Bay K 8644, that is a calcium channel blocker. In contrast, the increase in paired-pulse potentiation of the population spike, seen during the initial phase of ethanol withdrawal, was significantly decreased by both isomers of Bay K 8644. After the chronic ethanol treatment, single orthodromic stimuli produced epileptiform field potentials, consisting of two independent phases, a short latency series of multiple population spikes, superimposed upon the initial observed EPSP, and a longer latency train of spikes, occurring on a second EPSP, temporally distinct from the first. The (-) isomer of Bay K 8644 increased both these phases of epileptiform activity during ethanol withdrawal in a dose-dependent manner, while (+)-Bay K 8644 reduced the initial phase of multiple spiking and abolished the later phase. In slices from control animals, the higher concentration of (-)-Bay K 8644 (2 /sM), but not the lower concentration (500 nM) decreased the stimulation required to produce multiple population spikes. Neither produced the long latency epileptiform activity. The (+) isomer of Bay K 8644 had no effect on control recordings. Lesioning the Schaffer collateral-commissural fibre pathway, or removing area CA3, in slices from ethanol-treated animals, abolished the later phase of epileptiform activity without affecting the initial multiple spiking. Intracellular recordings from area CAl showed both the short latency and the longer latency epileptiform activities in slices from ethanol-treated mice and in control hippocampal slices after application of the (-) isomer of Bay K 8644, but these patterns of activity were not seen in control slices in the absence of Bay K 8644. Spontaneous activity during ethanol withdrawal was seen in intracellular recordings, but such activity was not seen in the field potential recordings. It is suggested that withdrawal from chronic ethanol treatment produced hyperexcitability in both area CAl and area CA3 of the isolated hippocampal slice, and that the epileptiform activity in area CA3 is effectively transmitted to area CAl. The effects of the isomers of Bay K 8644 suggested that this epileptiform activity was mediated, in part, by activity of dihydropyridinesensitive calcium channels.

Cav1.2 calcium channels modulate the spiking pattern of hippocampal pyramidal cells

“…Our findings in the Ca v 1.2 HKO mice as well as those obtained with DHP fit well with data from some earlier reports studying the role of L-type calcium channels by means of DHP (Whittington and Little, 1993;Pineda et al, 1998;Chen et al, 2005). For example, the DHP L-type channel blockers nifedipine Fig.…”

“…The role of L-type calcium channels in generating repetitive firing of neurons in the CNS is not clear. Studies with pharmacological tools yielded contradictory results (Moyer et al, 1992;Whittington and Little, 1993;Pineda et al, 1998;Chen et al, 2005) and, importantly, do not allow to discriminate between individual members of the L-type channel family. Here, we examined the intrinsic excitability of CA1 pyramidal cells from control mice and mice with the Ca v 1.2 gene inactivated in principal hippocampal neurons.…”

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

“…Besides several other factors (e.g. functional deficits of GABA receptors and increased VGCC function [77,212]), the NMDARs are major contributors to the increased glutamate release during alcohol withdrawal since in the brain of ethanol-dependent rats, the extracellular concentration of glutamate shows a transient, NMDAR mediated increase after cessation of ethanol intake and these changes are time-locked to the behavioural signs of ethanol withdrawal [44,53,183]. This enhanced glutamate release may contribute to the further shift towards the excitatory dominance in the CNS after ethanol withdrawal [184].…”

Chronic Benzodiazepine Administration Potentiates High Voltage-Activated Calcium Currents in Hippocampal CA1 Neurons

“…Ca 2ϩ current density was normalized and expressed as the percentage of the current evoked in the presence of vehicle. tion of L-type VGCC function, are involved in dependence on other central nervous system depressants such as ethanol, barbiturates, and morphine, as well as stimulants, including nicotine (Whittington and Little, 1993;Pourmotabbed et al, 1998;Rabbani and Little, 1999;Katsura et al, 2002). The finding that chronic, but not acute, benzodiazepine administration enhances HVA Ca 2ϩ currents suggests that a similar effect may occur in hippocampal CA1 pyramidal neurons associated with benzodiazepine withdrawal symptoms (Van Sickle et al, 2004).…”

“…VGCCs have been implicated in mediating synaptic plasticity associated with dependence on a wide range of central nervous system stimulants and depressants (Whittington and Little, 1993;Pourmotabbed et al, 1998;Rabbani and Little, 1999;Katsura et al, 2002Katsura et al, , 2005Katsura et al, , 2007Watson and Little, 2002;Rajadhyaksha and Kosofsky, 2005). Specifically, previous studies from our laboratory have demonstrated an enhancement of ␣-amino-3-hydroxy-5-methylisoxasole-4-propionic acid receptor (AMPAR) synaptic currents in hippocampal CA1 neurons Song et al, 2007), which was associated with anxiety-like behavior in benzodiazepine-withdrawn rats (Van Sickle et al, 2004;Xiang and Tietz, 2007).…”