Antiepileptic drugs combined with high-frequency electrical stimulation in the ventral hippocampus modify pilocarpine-induced status epilepticus in rats.

PURPOSE: To evaluate the effects of high-frequency electrical stimulation (HFS) in both ventral hippocampi, alone and combined with a subeffective dose of antiepileptic drugs, during the status epilepticus (SE) induced by lithium-pilocarpine (LP). METHODS: Male Wistar rats, stereotactically implanted in both ventral hippocampi, were injected with pilocarpine (30 mg/kg, i.p.) 24 h after lithium (3 mEq/kg) administration. One minute following pilocarpine injection, HFS (pulses of 60 mus width at 130 Hz at subthreshold intensities and applied during 3 h) was applied alone or combined with subeffective doses of antiepileptic drugs. RESULTS: HFS alone reduced the incidence of severe generalized seizures. This effect was not evident when HFS was combined with phenytoin (33.3 mg/kg, i.p.). HFS combined with diazepam (0.41 mg/kg, i.p.) or phenobarbital (10 mg/kg, i.p.) reduced the incidence of severe generalized seizures and mortality rate, and augmented the latency to first forelimb clonus, generalized seizure, and status epilepticus (SE). When combined with gabapentin (46 mg/kg, i.p.), HFS reduced the incidence of severe generalized seizures, enhanced latency to SE, and decreased mortality rate. DISCUSSION: Subeffective doses of antiepileptic drugs that increase the gamma-aminobutyric acid (GABA)ergic neurotransmission may represent a therapeutic tool to augment the HFS-induced anticonvulsant effects.

Behavioral effects of high frequency electrical stimulation of the hippocampus on electrical kindling in rats.

Experiments were designed to evaluate the effects of high frequency electrical stimulation (HFS) applied in ventral hippocampus during the hippocampal kindling process, as well as on the expression of fully kindled seizures and the refractoriness for subsequent convulsions during their postictal period. Male Wistar rats, stereotactically implanted in both ventral hippocampus, received daily bilateral HFS (pulses of 60 micros width at 130 Hz at subthreshold current intensity) during 1h immediately after each kindling stimulation (1s train of 60 Hz biphasic square waves, each 1 ms) during 40 days or until the kindled state was achieved. Rats were classified as follows: (a) Responder animals, who required low current intensity for HFS (208+/-38.2 microA), did not show progress of the kindling process and remained in stages II and III seizures. (b) Nonresponders rats, in which the current intensity for HFS was higher (434.5+/-51.7 microA), developed the kindling process as the kindling control group. When HFS was applied before the kindling stimulation in fully kindled rats, animals presented a reduced expression of the fully kindled seizures (nonresponders animals) and an enhanced refractoriness for subsequent seizures during the postictal period (kindling control and nonresponder animals). There was no correlation between the area where the HFS was applied and the effects induced. It was concluded that HFS at 130 Hz in ventral hippocampus is able to modify the epileptogenesis induced by the hippocampal kindling process and the refractoriness to subsequent seizures during the postictal period in rats.

GABA and opioid binding distribution in the brain of the seizure-resistant Proechimys guyannensis: an autoradiography study.

Proechimys guyannensis rodents present resistance to epilepsy. Autoradiography was used to map GABA(A) ((3)H-Muscimol), benzodiazepine ((3)H-Flunitrazepam), mu ((3)H-DAMGO), and delta ((3)H-DPDPE) opioid receptor binding in adult Proechimys guyannensis brain under normal conditions. Results were compared with values obtained from adult Wistar rats. Proechimys presented reduced (3)H-Muscimol binding in several cortices, thalamus, medial amygdala nucleus, and dorsal dentate gyrus. (3)H-Flunitrazepam binding was reduced in periaqueductal gray, frontal and entorhinal cortices, and enhanced in piriform cortex and ventral CA2 field of Ammons horn. Concerning (3)H-DAMGO binding, high values were found in several cortices, medial amygdala nucleus, dorsal dentate gyrus, and periaqueductal gray, whereas reduced binding was detected in anterior olfactory tubercle, cingulated cortex, thalamus, basolateral amygdala, substantia nigra, and dorsal and ventral CA fields. High (3)H-DPDPE binding was noticed in CA1 field from dorsal hippocampus, while reduced values were found in cingulate cortex, olfactory tubercle, thalamus, and substantia nigra. These findings provide the first description of receptor binding distribution of the Proechimys brain and suggest natural endogenous anticonvulsant mechanisms of theses rodents under normal conditions.

An improved method for long-term measuring of hemolymph fluctuations of non-essential amino acids, GABA and histamine from freely moving crayfish.

The microdialysis method was adapted to obtain long-term hemolymph dialysates from the pericardial cavity of freely moving Procambarus clarkii crayfish, to measure fluctuations of non-essential amino acids, GABA and histamine by high-performance liquid chromatography using off-line fluorometric derivatization. Asp, Ala, Tau, GABA and histamine (HA) reached its maximal concentrations at the daybreak, whereas glutamate (Glu), Gln and Gly peaked at the end of the light period. The minimum and maximal detected amounts for each substance along the 24h cycle were (in microM): 20-300Asp, 100-200Glu, 400-700Gln, 400-600Gly, 100-200Tau, 150-300Ala, 2-10 GABA and 25-250HA. Cocktails containing the relative concentration of each amino acid, GABA and histamine resulted in a hyperpolarization that reduced the spontaneous firing of cultured peptidergic X organ neurons. Glu, GABA and histamine evoked a long-lasting hyperpolarization that suppressed the spontaneous firing, whereas Asp, Gly and Tau evoked a depolarization accompanied with neuronal firing. Finally, neither Ala nor Gln modified the resting membrane potential.

5-HT1A receptor agonists modify epileptic seizures in three experimental models in rats.

The effects of two serotonergic (5-HT1A) receptor agonists (8-OH-DPAT; 0.01, 0.1, 0.3, 1 mg/kg, s.c., and Indorenate; 1, 3, 10 mg/kg, i.p.) were evaluated in three type of seizures in male Wistar rats: clonic-tonic convulsions induced by pentylenetetrazol (PTZ, 60 mg/kg, i.p.), status epilepticus (SE) of limbic seizures produced by kainic acid (KA, 10 mg/kg, i.p.) and tonic-clonic seizures by amygdala kindling. 8-OH-DPAT decreased the incidence of tonic seizures and the mortality rate induced by PTZ. Indorenate increased the latency to the PTZ-induced seizures and decreased the percentage of rats showing tonic extension and death. Concerning KA, 8-OH-DPAT augmented the latency and reduced the frequency of wet-dog shake (WDS) and generalized seizure (GS). At high doses it diminished the occurrence and delayed the establishment of SE. Indorenate augmented the latency to WDS, GS and SE, and diminished the number of GS. 8-OH-DPAT and Indorenate did not alter the expression of kindled seizures. However, Indorenate enhanced the refractoriness to subsequent seizures during the postictal depression. Some effects induced by 8-OH-DPAT and Indorenate on seizures evaluated and postictal depression were fully or partially blocked by WAY100635. These results suggest that 5-HT1A receptor agonists modify epileptic activity depending on the type of seizure.