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This study assessed the effects of drugs which manipulate the cAMP system on afterdischarges (ADs) induced in the CA1 region of rat hippocampal slices. The adenylate cyclase activator forskolin (50 microM) and the phosphodiesterase inhibitor rolipram (0.1 and 1 microM) enhanced AD generation. These effects were reversed by the cAMP-dependent protein kinase inhibitors H-89 (5 microM) and Rp-cAMPS (100 microM). These findings suggest that AD generation can be modulated through cAMP generation and the subsequent activation of the cAMP-dependent protein kinase., (Copyright 2002 Elsevier Science B.V.)

It has been hypothesized that a disruption of gamma-aminobutyric acid (GABA) receptor-mediated processes may be involved in the pathophysiology of focal epilepsy. This disinhibition hypothesis has been postulated from the results of in vitro experiments of the interictal activity of focal epilepsy. Less is known, however, about how disinhibition may be involved in the production of the ictal activity. We therefore examined the pharmacological effects of selective agonists and antagonists of GABA(A) and GABA(B) receptors on ictal-like afterdischarges (ADs) induced following repetitive high-frequency electrical stimulation in the CA1 region of rat hippocampal slices. The GABA(A) receptor antagonist bicuculline (5 microM) fully blocked AD generation, as did the GABA(A) receptor agonist muscimol (2 microM), which is thought to produce a tonic inhibition during application. However, the benzodiazepine receptor agonist diazepam (5 microM), which enhances the inhibitory postsynaptic potential induced by synaptically released GABA, increased the number of spikes in the AD to 148.3% of the control value. On the other hand, the GABA(B) receptor antagonist phaclofen (1 mM) increased the number of spikes in the AD to 234.7% of the control value, while the GABA(B) receptor agonist baclofen (5 microM) reduced it to 46.9%. We therefore conclude that synaptic, but not tonic, activation of GABA(A) receptors appears to be necessary for ictal-like AD generation, while GABA(B) receptor activation plays a protective role. We therefore propose a modification to the simple disinhibition hypothesis.

To clarify the possible involvement of Ca2+ channel subtypes in epileptogenesis, the CA1 region of rat hippocampal slices was examined for the pharmacological effects of Ca2+ channel blockers on ictal-like afterdischarges (ADs) observed following the repetition of high-frequency electrical stimulation, as well as on interictal-like bursts of population spikes following single stimuli in the presence of bicuculline. Ni2+ and amiloride, which predominantly block T-type Ca2+ channels, suppressed the number of spikes in ADs at concentrations of these two channel blockers sufficient to eliminate this type of Ca2+ channel in acutely dissociated and cultured hippocampal neurons. On the other hand, neither the L-type Ca2+ channel blocker nifedipine nor the N-type Ca2+ channel blocker City, omega-conotoxin GVIA had any effect on the generation of ADs. In addition, none of these T-, L- and N-type channel blockers had any effect on the bicuculline-induced, interictal-like epileptiform discharges. We therefore conclude that the activation of T-type Ca2+ channels, which is distinct from the mechanisms involved in interictal activity, may play a causative role in the generation of ictal-like ADs., (Copyright 1998 Elsevier Science B.V.)

This study assessed the action of the serotonin3 (5-HT3) receptor agonist, 1-(m-chlorophenyl)-biguanide (m-CPBG), against both kindled seizures and kindling development from the rat amygdala (AM). The intracerebroventricular (i.c.v.) administration of 40 microg m-CPBG significantly increased the duration of afterdischarge and bilateral forelimb clonus of generalized kindled seizures. In addition, daily i.c.v. treatment with m-CPBG at the same dose prior to each electrical stimulation to the AM significantly facilitated behavioral and electrographic seizure development and reduced the number of stimulations needed to elicit generalized seizures. The present results indicate that m-CPBG increases the duration of fully kindled seizures and facilitates the developmental seizure process, suggesting an excitatory role of 5-HT3 receptors in the kindling model of epilepsy.

The present study was conducted to identify serotonin (5-HT) receptor subtypes involved in the development of amygdala (AM) kindling. We used 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A agonist, and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2 agonist, both of which were injected subcutaneously 15 min prior to each daily electrical stimulation to the rat AM. Treatment with 8-OH-DPAT (1 mg/kg) slightly suppressed behavioral and electrographic seizure development during the course of kindling. In contrast, DOI (1 mg/kg) strongly facilitated kindling development and reduced the number of stimulations needed to produce generalized seizures. These facilitatory effects of DOI were completely blocked by pretreatment with a 5-HT2 antagonist ketanserin. The present results suggest that the activation of 5-HT1A receptors can retard the development of AM kindling, whereas 5-HT2 receptors play a facilitatory role in this developmental seizure process.