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Low frequency stimulation (LFS) has anticonvulsant effect and may restore the ability of long-term potentiation (LTP) to the epileptic brain. The mechanisms of LFS have not been completely determined. Here, we showed that LTP induction was impaired following in vitro epileptiform activity (EA) in hippocampal slices, but application of LFS prevented this impairment. Then, we investigated the involvement of α-adrenergic receptors in this effect of LFS. EA was induced by increasing the extracellular K+ concentration to 12 mM and EPSPs were recorded from CA1 neurons in whole cell configuration. EA increased EPSP amplitude from 6.9 ± 0.7 mV to 9.6 ± 0.6 mV. For LTP induction, the Schaffer collaterals were stimulated by high frequency stimulation (HFS; two trains of 100 pulses, 100 Hz at the interval of 20 s). The application of HFS resulted in 40.9 ± 2.3% increase in the amplitude of EPSPs. However, following EA, HFS could not produce any significant changes in EPSP amplitude. Administration of LFS (1 Hz, 900 pulses) to Schaffer collaterals at the beginning of EA restored LTP induction to the hippocampal slices and HFS increased the EPSPs amplitude up to 41.7 ± 3.1% of baseline. When slices were perfused by prazosin (α 1 -adrenergic receptor antagonist; 10 μM) before and during LFS application, LFS improvement on LTP induction was reduced significantly. Perfusion of slices by yohimbine (α 2 -adrenergic receptor antagonist; 5 μM) had no effect on LFS action. Therefore, it may be concluded that following epileptiform activity, LFS can improve the impairment of LTP generation through α 1 , but not α 2 , adrenergic receptor activity. Unlabelled Image • High-K + induced epileptiform activity (EA) was induced in hippocampal slices. • EA lead to impairment in LTP generation by high frequency stimulation. • LFS reduced the duration of EA and returned the ability of LTP induction. • This effect of LFS was mediated through α 1 but not α 2 receptors activity. [ABSTRACT FROM AUTHOR]

• Kindled animals show impairment in learning & memory. • Low-frequency electrical stimulation (LFS) improves learning & memory impairment. • LFS induced memory improvement is reduced by hippocampal 5-HT 1A antagonist. • LFS also prevented the kindling-induced increase in 5-HT 1A receptors. In addition to its anticonvulsant effect, low frequency stimulation (LFS) improves learning and memory in kindled animals. In the present study, the role of 5-HT 1A receptors in mediating LFS' improving effect on spatial learning and memory was investigated in amygdala-kindled rats. Amygdala kindling was conducted in a semi-rapid kindling stimulations (12 stimulations per day) in male Wistar rats. LFS (4 trains of 0.1 ms pulse duration at 1 Hz, 200 pulses, 50–150 μA, at 5 min intervals) was applied after termination of kindling stimulations. NAD-299 (a selective 5-HT 1A receptor antagonist; 2.5 and 5 μg/μl) was microinjected into the hippocampal CA1 before applying LFS. The Morris water maze, and novel object recognition tests were conducted after the last kindling stimulation. Hippocampal samples were also prepared, and 5-HT 1A receptor gene expression levels were assessed using quantitative RT-PCR. In kindled animals, LFS reduced impairments in spatial learning and memory in the Morris water maze and novel object recognition tests. Microinjection of NAD doses of 5 μg/μl reduced the effects of LFS on learning and memory. The gene expression level of 5-HT 1A receptors increased significantly in the hippocampus of amygdala-kindled rats. However, LFS applied after kindling stimulations inhibited this effect. It seems that activation of 5-HT 1A receptors in the CA1 field is necessary for LFS' improving effects on spatial learning and memory in kindled animals; although surprisingly, LFS application prevented the elevation in gene expression of 5-HT 1A receptors in kindled animals. [ABSTRACT FROM AUTHOR]

Abstract Low frequency stimulation (LFS) has been proposed as a method in the treatment of epilepsy, but its anticonvulsant mechanism is still unknown. In the current study, the hippocampal CA1 region was microinjected with NAD-299 (a selective 5-HT 1A antagonist), and its role in mediating the inhibitory action of LFS on amygdala kindling was investigated. Male Wistar rats were kindled by amygdala stimulation in a semi-rapid kindling manner (12 stimulations per day). LFS (0.1 ms pulse duration at 1 Hz, 200 pulses, 50–150 μA) was applied at 5 min after termination of daily kindling stimulations. NAD (a selective 5-HT 1A antagonist) was microinjected into the CA1 region of the hippocampus at the doses of 2.5 and 5 μg/1 μl. An open field test was also run to determine the motor activity of animals in different experimental groups. The application of LFS following daily kindling stimulations reduced the behavioral seizure stages, afterdischarge duration, and stage 5 seizure duration and increased the latency to stage 4 seizure compared to the kindled group. However, microinjection of NAD at the doses of 5 μg/1 μl, but not 2.5 μg/1 μl, blocked the inhibitory effect of LFS on behavioral and electrophysiological parameters in kindled animals. It could be presumed that 5-HT 1A receptors in the CA1 area are involved in mediating the antiepileptic effects of LFS. Highlights • Low frequency stimulation (LFS) was applied into the amygdala of kindled rats. • LFS application in amygdala decreased afterdischarge duration in kindled rats. • LFS in amygdala reduced behavioral seizure stages. • Intrahippocampal 5-HT1A antagonist prevented the inhibitory effect of LFS. [ABSTRACT FROM AUTHOR]