Electroconvulsive Threshold In Mice Research Articles

Amiodarone, a multi-channel blocker, enhances anticonvulsive effect of carbamazepine in the mouse maximal electroshock model

Cardiac arrhythmia may occur in the course of epilepsy. Simultaneous therapy of the two diseases might be complicated by drug interactions since antiarrhythmic and antiepileptic agents share some molecular targets. The aim of this study was to evaluate the influence of amiodarone, an antiarrhythmic drug working as a multi-channel blocker, on the protective activity of four classical antiepileptic drugs in the maximal electroshock test in mice. Amiodarone at doses up to 75 mg/kg did not affect the electroconvulsive threshold in mice. Acute amiodarone at the dose of 75 mg/kg significantly potentiated the anticonvulsive effect of carbamazepine, but not that of valproate, phenytoin or phenobarbital in the maximal electroshock-induced seizures in mice. The antiarrhythmic agent and its combinations with antiepileptic drugs did not impair motor performance or long-term memory in mice, except for the combination of amiodarone and phenobarbital. Brain concentrations of antiepileptic drugs were not changed. Despite favourable impact of amiodarone on the anticonvulsive action of carbamazepine in the maximal electroshock, co-administration of the two drugs should be carefully monitored in clinical conditions. Further studies are necessary to evaluate effects of chronic treatment with amiodarone on seizure activity and the action of antiepileptic drugs.

Effect of amlodipine on the antiepileptic action of lamotrigine, gabapentin and topiramate on maximal electroshock induced seizures in mice

Background: The development of newer classes of antiepileptic drugs has created several opportunities for the treatment of epilepsy. Aims & Objective: The present study was designed to assess the$effect of amlodipine on the antiepileptic action of lamotrigine, gabapentin and topiramate in the mouse maximal electroshock-induced seizure model. Materials and Methods: 300 Adult male mice were divided into 8 groups: (1) control to determine CS50; (2) amlodipine at doses of 5 mg/kg, 10 mg/kg and 20 mg/kg; (3) to determine ED50 of lamotrigine alone; (4) to determine ED50 of lamotrigine after amlodipine; (5) to determine ED50 of gabapentin alone; (6) to determine ED50 of gabapentin after amlodipine; (7) to determine ED50 of topiramate alone; (8) to determine ED50 of topiramate after amlodipine. Results: It was found that amlodipine (up to 20 mg/kg), did not affect the electroconvulsive threshold in mice thus, it has no anticonvulsant effect. Moreover, amlodipine at doses of 10 and 20 mg/kg significantly enhanced the antiseizure action of the three anti convulsant drugs. Amlodipine through the blockade of N- and P/Q type calcium channels enhances the effects of lamotrigine related to the reduction of glutamate release from neurons. It binds to the alpha2 sigma subunit of voltage gated calcium channels, this may explain the observed interaction between gabapentin and amlodipine in the maximal electroshock-induced seizures in mice. Topiramate inhibits voltage-dependent sodium and L-type calcium channels. Its effect on calcium channels may explain the interaction with amlodipine. Conclusion: Amlodipine potentiates the anticonvulsant action of lamotrigine, gabapentin and topiramate.

Isobolographic characterization of interactions between vigabatrin and tiagabine in two experimental models of epilepsy

To characterize the type of interactions between vigabatrin (VGB) and tiagabine (TGB) — two newer antiepileptic drugs influencing GABA-ergic neurotransmitter system, the isobolographic analysis was used in two experimental models of epilepsy: the maximal electroshock seizure threshold (MEST) test and pentylenetetrazole (PTZ)-induced seizures in mice. Results indicated that VGB and TGB administered separately (i.p.) increased the electroconvulsive threshold in mice, which allowed the calculation of their TID 20 values (threshold increasing doses by 20% over the threshold of control animals) in the MEST test. The TID 20 for VGB was 226.2 mg/kg and that for TGB was 4.4 mg/kg. With isobolography, the combinations of VGB with TGB (at fixed-ratios of 1:3, 1:1 and 3:1) exerted additive interactions in the MEST test in mice. Similarly, VGB and TGB injected separately (i.p.) suppressed the PTZ-induced seizures, and their ED 50 values (median effective doses, protecting 50% of the animals tested against clonic convulsions) for VGB and TGB were 622.5 mg/kg and 0.8 mg/kg, respectively. Isobolographic analysis of interactions revealed that the combinations of VGB with TGB at the fixed-ratios of 1:3 and 1:1 produced supra-additive (synergistic) interactions against PTZ-induced seizures. Only the combination of VGB with TGB at the fixed-ratio of 3:1 was additive in the PTZ test. The evaluation of acute adverse-effect potential for all fixed-ratio combinations of VGB with TGB (administered at their TID 20 and ED 50 values from the MEST and PTZ tests) revealed that none of the examined combinations affected motor coordination in the chimney test and altered neuromuscular tone in the grip-strength test in mice. In contrast, VGB in combinations with TGB produced the antinociceptive effects with respect to suppression of acute thermal pain in animals subjected to the hot-plate test. Based on this preclinical study, one can ascertain that the combination of VGB with TGB would provide an adequate seizure control in epileptic patients.

Arachidonyl-2′-chloroethylamide, a highly selective cannabinoid CB 1 receptor agonist, enhances the anticonvulsant action of valproate in the mouse maximal electroshock-induced seizure model

Endogenous cannabinoid ligands and cannabinoid CB 1 receptor agonists have been shown to exert potent anticonvulsant effects in various experimental models of epilepsy. The purpose of this study was to determine the effects of arachidonyl-2′-chloroethylamide (ACEA; N-(2-chloroethyl)-5 Z,8 Z,11 Z,14 Z-eicosatetraenamide, a highly selective cannabinoid CB 1 receptor agonist) on the threshold for electroconvulsions and the anticonvulsant activity of valproate in the maximal electroshock-induced seizures in mice. To inhibit the rapid metabolic degradation of ACEA by the fatty-acid amide hydrolase, phenylmethylsulfonyl fluoride (PMSF) was used at a constant ineffective dose of 30 mg/kg (i.p.). Moreover, the effects of ACEA and PMSF on the acute adverse-effect profile of valproate were determined in the chimney test. Additionally, the adverse-effect potentials of combination of ACEA, PMSF with valproate were examined in the step-through passive avoidance task (long-term memory) and grip-strength test (neuromuscular strength). To ascertain any pharmacokinetic contribution of ACEA and PMSF to the observed interaction between tested drugs, both free (non-protein bound) plasma and total brain concentrations of valproate were estimated. Results indicated that ACEA (5 and 7.5 mg/kg; i.p.) combined with PMSF increased significantly ( P < 0.001) the electroconvulsive threshold in mice. ACEA at low doses of 1.25 and 2.5 mg/kg, i.p., with PMSF had no impact on threshold for electroconvulsions. Similarly, neither PMSF (30 mg/kg) nor ACEA (15 mg/kg) administered alone affected the electroconvulsive threshold in mice. Moreover, ACEA (at a subthreshold dose of 2.5 mg/kg; i.p.) co-administered with PMSF potentiated significantly the antielectroshock activity of valproate by reducing its ED 50 from 258.3 to 195.1 mg/kg ( P < 0.01). Isobolographic transformation of data revealed that the interactions between valproate and ACEA (at 1.25 and 2.5 mg/kg) combined with PMSF were additive. In the chimney test, the combination of ACEA (2.5 mg/kg) and PMSF (30 mg/kg) had no effect on acute adverse effect of valproate and its TD 50 (356.4 mg/kg) did not differ significantly from that for valproate administered alone (TD 50 = 404.4 mg/kg). Moreover, none of the examined drugs administered either alone or in combinations produced long-term memory deficits in the step-through passive avoidance task and impaired neuromuscular strength in the grip-strength test in mice. In contrast, ACEA (2.5 mg/kg; i.p.) combined with PMSF (30 mg/kg; i.p.) considerably increased both, the free plasma (by 42%; P < 0.01) and total brain (by 49%; P < 0.001) concentrations of valproate (administered at 195 mg/kg; i.p.) in mice. Hence, the observed interaction between valproate and ACEA with PMSF in the maximal electroshock test was pharmacokinetic in nature. Finally, based on this preclinical study, one can conclude that ACEA — a cannabinoid CB 1 receptor agonist co-administered with PMSF pharmacokinetically interacted with valproate and thus, providing the enhancement of the antielectroshock activity of valproate in mice, although, the isobolographically determined interaction between drugs was additive. To elucidate the protective role of cannabinoids in the brain during seizures, more advanced neurochemical studies are required.

2-Phosphonomethyl-pentanedioic acid (glutamate carboxypeptidase II inhibitor) increases threshold for electroconvulsions and enhances the antiseizure action of valproate against maximal electroshock-induced seizures in mice

This study examined the effect of 2-(phosphonomethyl)-pentanedioic acid (2-PMPA), a potent and selective inhibitor of glutamate carboxypeptidase II (GCP II), an enzyme releasing glutamate and N-acetyl-aspartate from synaptical terminals, on the electroconvulsive threshold in mice. Moreover, the influence of 2-PMPA on the anticonvulsant activities of four conventional antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) was evaluated in the maximal electroshock-induced seizure test in mice. Results indicated that 2-PMPA (at a dose range of 50–200 mg/kg, i.p.) raised the electroconvulsive threshold in mice dose-dependently. Linear regression analysis of dose–response relationship between the doses of 2-PMPA and their corresponding threshold values allowed the calculation of threshold increasing dose by 20% (TID 20), which was 109.2 mg/kg. Moreover, 2-PMPA administered i.p. at a constant dose of 150 mg/kg (the dose increasing the threshold for electroconvulsions) enhanced significantly the anticonvulsant action of valproate, by reducing its median effective dose (ED 50) from 281.4 to 230.1 mg/kg ( P < 0.05). In contrast, 2-PMPA at the lower dose of 100 mg/kg (i.p.) had no impact on the antiseizure activity of valproate in the maximal electroshock-induced seizure test. Likewise, 2-PMPA at 100 and 150 mg/kg did not affect the antiseizure action of carbamazepine, phenobarbital and phenytoin against maximal electroshock-induced seizures in mice. Additionally, none of the combinations investigated between 2-PMPA (150 mg/kg, i.p.) and carbamazepine, phenobarbital, phenytoin and valproate (at their ED 50 values) produced motor coordination impairment in the chimney test. Pharmacokinetic evaluation of interaction between 2-PMPA and valproate revealed that 2-PMPA at 150 mg/kg selectively increased total brain concentrations of valproate, remaining simultaneously without any effect on free plasma concentrations of valproate, indicating a pharmacokinetic nature of observed interaction in the maximal electroshock-induced seizures in mice. Based on our preclinical data, it may be concluded that 2-PMPA possesses a seizure modulating property by increasing the electroconvulsive threshold. The reduction of glutamate neurotransmission in the brain, as a consequence of inhibition of GCP II activity by 2-PMPA, was however insufficient to enhance the anticonvulsant activity of conventional antiepileptic drugs, except for valproate, whose antiseizure action against maximal electroconvulsions was potentiated by 2-PMPA. Unfortunately, the favourable interaction between 2-PMPA and valproate was associated with a pharmacokinetic increase in total brain valproate concentrations.

1-Methyl-1,2,3,4-tetrahydroisoquinoline enhances the anticonvulsant action of carbamazepine and valproate in the mouse maximal electroshock seizure model

1-Methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTHIQ – an endogenous parkinsonism-preventing substance) administered intraperitoneally at a dose of 20 mg/kg considerably elevated the threshold for electroconvulsions in mice from 6.4 to 8.4 mA ( P < 0.05). In contrast, the agent administered at 5 and 10 mg/kg had no significant impact on the electroconvulsive threshold in mice. Moreover, 1-MeTHIQ (at a subthreshold dose of 10 mg/kg) potentiated the anticonvulsant action of valproate (VPA) against maximal electroshock (MES)-induced seizures in mice, reducing its median effective dose (ED 50) from 232 to 170 mg/kg ( P < 0.001). Similarly, 1-MeTHIQ (at 10 mg/kg) enhanced the antielectroshock activity of carbamazepine (CBZ) in mice, decreasing its ED 50 from 10.8 to 7.8 mg/kg ( P < 0.05). In contrast, 1-MeTHIQ (at 10 mg/kg) did not affect the anticonvulsant action of phenytoin and phenobarbital against MES-induced seizures in mice. The evaluation of acute neurotoxic effects of the studied antiepileptic drugs (AEDs) in combination with 1-MeTHIQ, as regards motor coordination impairment in the chimney test, revealed no significant changes in median toxic doses (TD 50) of conventional AEDs after systemic administration of 1-MeTHIQ (up to 10 mg/kg). Pharmacokinetic characterization of interactions between 1-MeTHIQ (10 mg/kg) and VPA (170 mg/kg) or CBZ (7.8 mg/kg) revealed no significant changes in total brain concentrations of CBZ and VPA, indicating that the observed enhancement of antiseizure effects of CBZ and VPA by 1-MeTHIQ was pharmacodynamic in nature. Based on our preclinical study, it may be concluded that 1-MeTHIQ exerts the anticonvulsant effects increasing the threshold for electroconvulsions and potentiating the antiseizure action of CBZ and VPA against maximal electroshock. The antiseizure properties of 1-MeTHIQ (an endogenous parkinsonism-preventing substance) and its exact physiological role in the brain need extensive examination in further neuropharmacological studies.

Interactions between riluzole and conventional antiepileptic drugs – a comparison of results obtained in the subthreshold method and isobolographic analysis

The exact types of pharmacodynamic interactions between riluzole and conventional antiepileptic drugs were evaluated in two available ways, the subthreshold and isobolographic analysis. Maximal electroshock test in mice was used as an animal model for generalized tonic-clonic convulsions. In the first method, riluzole (1.25-2.5 mg/kg) significantly raised the electroconvulsive threshold in mice. The drug administered at its subprotective dose of 0.3125 mg/kg enhanced the antiseizure activity of carbamazepine and phenobarbital, while, when applied at the higher dose of 0.625 mg/kg, it potentiated also the action of valproate and diphenylhydantoin. Riluzole (0.625) alone and in combinations with antiepileptic drugs did not produced any motor or log-term memory deficit. Results obtained from isobolographic analysis determined pure additive interaction between riluzole and all used conventional antiepileptic drugs. Since riluzole did not change plasma concentrations of co-administered antiepileptics, pharmacokinetic interactions, at least in terms of their free plasma levels, do not seem probable. The results of the present study confirm significant antiseizure properties of riluzole in the model of generalized tonic-clonic epileptic attacks. Moreover, comparison of effects obtained from both methods evaluating drug interactions strongly indicates a crucial role of the isobolographic analysis in verification and supplementation data achieved from the subthreshold method.

Influence of the combined treatment of LY 300164 (an AMPA/kainate receptor antagonist) with adenosine receptor agonists on the electroconvulsive threshold in mice

7-Acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7 H-1,3-dioxolo-4,5 H-2,3-benzodiazepine hydrochloride (LY 300164; a selective noncompetitive AMPA/kainate antagonist; 2 mg/kg) and N 6-2-(4-aminophenyl)ethyl-adenosine (APNEA; a nonselective adenosine A 1/A 3 receptor agonist; 2 and 3 mg/kg) significantly raised the threshold for electroconvulsions in mice. In contrast, 5′- N-ethylcarboxamidoadenosine (NECA; a nonselective adenosine A 1/A 2 receptor agonist; up to 1 mg/kg) did not affect the electroconvulsive threshold. The combined treatment of LY 300164 with NECA or APNEA was superior to single-drug medication as regards their protective action in this seizure model. Moreover, the combinations of LY 300164 with either NECA or APNEA were devoid of motor impairment, although they produced a significant long-term memory deficit. Measurement of the plasma levels of LY 300164 alone and in combination with APNEA or NECA did not suggest pharmacokinetic phenomena as an explanation for the interaction between these drugs. APNEA did not influence the plasma concentration of LY 300164. Moreover, NECA even significantly decreased the plasma levels of the AMPA/kainate antagonist. The present study clearly indicates a strong positive interaction in terms of anticonvulsant activity between LY 300164 and the drugs acting via adenosine receptors.

Interactions of tiagabine with some antiepileptics in the maximal electroshock in mice

Tiagabine (TGB), a new potent γ-aminobutyric acid (GABA) uptake inhibitor, is widely applied in adjunctive treatment of partial seizures in humans. Although, polytherapy is not an initial method of epilepsy treatment, clinicians often combine TGB with other antiepileptics as add-on therapy for assuring the anticonvulsant protection in patients with refractory seizures. To evaluate the character of pharmacological interactions between TGB and some antiepileptics, the isobolographic analysis was used as a suitable method for determining the exact types of interactions. Determination of an influence of TGB on the protective effects of diphenylhydantoin (DPH), carbamazepine (CBZ), valproate (VPA), phenobarbital (PB), lamotrigine (LTG), topiramate (TPM), and felbamate (FBM) in maximal electroshock-induced seizures was essential for this study. To exclude or confirm a pharmacokinetic character of observed interactions, the free plasma and brain concentrations of antiepileptic drugs (AEDs) studied were evaluated by using the immunofluorescence or high-pressure liquid chromatography (HPLC). TGB (up to 2.5 mg/kg) remained ineffective upon the electroconvulsive threshold, whilst the drug in doses of 5 and 10 mg/kg significantly raised the electroconvulsive threshold in mice. According to the isobolography, TGB appears to act synergistically with VPA. The remaining combinations tested exerted additive interactions. A pharmacokinetic character of interaction between TGB and VPA was evidently corroborated either in plasma or brains. Moreover, TGB significantly reduced the plasma and brain concentrations of DPH; however, pharmacokinetic events were not accompanied by any changes in anticonvulsant activity of the latter. Finally, the isobolographic analysis revealed that combinations of TGB with VPA exerted synergistic (supra-additive) interaction resulting from a pharmacokinetic interaction.

INFLUENCE OF 3-PPP, A SIGMA RECEPTOR LIGAND, ON THE ANTICONVULSIVE ACTION OF CONVENTIONAL ANTIEPILEPTIC DRUGS

(+)-3-(3-Hydroxyphenyl)- N -(1-propyl)-piperidine (3-PPP; a sigma receptor ligand), administered at 30 mg kg−1, 30 min before the test, significantly decreased the electroconvulsive threshold in mice, being ineffective in lower doses. 3-PPP (20 mg kg−1) diminished the protective activity of diphenylhydantoin, phenobarbital and valproate, but not that of carbamazepine against maximal electroshock. The effect of 3-PPP upon the electroconvulsive threshold and the 3-PPP-induced inhibition of the protective action of antiepileptics was reversed by haloperidol (0.5 mg kg−1). Moreover, 3-PPP did not alter the total and free plasma levels of antiepileptic drugs, so a pharmacokinetic interaction is not probable. The combined treatment of 3-PPP with antiepileptic drugs, providing a 50% protection against maximal electroshock, did not affect motor performance in mice, although resulted in significant long-term memory deficits. Our data indicate that sigma receptor-mediated events may play some role in seizure processes in the central nervous system and can modulate the protective activity of some conventional antiepileptic drugs.pc 1999 Academic Press@p$hr

Influence of melatonin upon the protective action of conventional anti-epileptic drugs against maximal electroshock in mice

Melatonin (50 mg/kg; 60 min before the test) significantly raised the electroconvulsive threshold in mice. The protective action of melatonin (50 mg/kg) in the electroconvulsive threshold test was reversed by aminophylline, picrotoxin and bicuculline. Melatonin at the subconvulsive dose of 25 mg/kg potentiated the anticonvulsive activity of carbamazepine and phenobarbital (ED 50 values were significantly decreased from 12.1 to 8.3 and from 18.9 to 11.8 mg/kg, respectively). No potentiation was observed in the case of valproate and diphenylhydantoin (their ED 50s were changed from 253 to 249 and from 10.3 to 9.7 mg/kg, respectively). Melatonin did not influence the plasma or brain levels of anti-epileptics studied, so a pharmacokinetic interaction is not probable. Melatonin (25 mg/kg) alone and its combinations with carbamazepine or phenobarbital, providing a 50% protection against maximal electroshock, were devoid of significant motor adverse effects, but caused strong long-term memory deficit. Consequently, it does not seem to be a good candidate for the treatment of epilepsy.

Influence of isradipine, niguldipine and dantrolene on the anticonvulsive action of conventional antiepileptics in mice

We report the effects of two new dihydropyridine derivatives, isradipine (4-(4′-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methylisopropylester) and niguldipine (1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinecarboxylic acid 3-(4,4-diphenyl-1-piperidinyl)-propyl methyl ester hydrochloride), and of dantrolene (1-{(5-{ p-nitrophenyl}furfurylidene)-amino}hydantoin sodium, an inhibitor of Ca 2+ release from intracellular stores) on the protective efficacy of antiepileptic drugs against maximal electroshock-induced seizures. It was shown that dantrolene (5–20 mg/kg), isradipine (5–10 mg/kg) and niguldipine (up to 2.5 mg/kg) did not influence the electroconvulsive threshold in mice, although a higher dose of niguldipine (5 mg/kg) significantly elevated it. Dantrolene (10–20 mg/kg) and isradipine (1 mg/kg) did not affect the anticonvulsive activity of conventional antiepileptic drugs. In contrast, niguldipine (2.5–5 mg/kg) impaired the protective action of carbamazepine and phenobarbital. No effect of niguldipine (2.5–5 mg/kg) was observed upon the anticonvulsive efficacy of diphenylhydantoin and valproate. BAY k-8644 (methyl-1,4-dihydro-2,6-dimethyl-5-nitro-4-{(2-trifluoromethyl)-phenyl}-pyridine-5-carboxylate, an L-type Ca 2+ channel agonist) did not reverse the action of niguldipine alone or the niguldipine-induced impairment of the anticonvulsive action of carbamazepine and phenobarbital. Niguldipine did not influence the free plasma levels of carbamazepine and phenobarbital, so a pharmacokinetic interaction is not probable. The results suggest that in contrast to the anticonvulsive activity of niguldipine against electroconvulsions, this Ca 2+ channel inhibitor significantly weakened the protective action of both carbamazepine and phenobarbital. These effects do not seem to result from the blockade of voltage-dependent Ca 2+ channels. Isradipine and dantrolene did not have a modulatory action on the threshold for electroconvulsions or on the anticonvulsive activity of antiepileptic drugs. It may be concluded that the use of niguldipine, isradipine, and dantrolene in epileptic patients seems questionable. © 1997 Elsevier Science B.V. All rights reserved.

Interaction of mu-opioid antagonistic drugs with antiepileptics.

Interactions of the mu-opioid receptor antagonists, naloxone (0.3 and 1 mg/kg), cyprodime and clocinnamox (3 and 10 mg/kg for both drugs) with phenytoin (7 mg/kg), phenobarbital (7 mg/kg), carbamazepine (10 mg/kg) and valproic acid (130 mg/kg) were investigated using the electroconvulsive threshold in mice as a model in order to elucidate a possible role of mu-receptor mediated reactions in the mechanism of action of antiepileptic drugs. All 3 mu-antagonists are devoid of an effect on the electroconvulsive threshold. Pretreatment with the mu-antagonists resulted partly in an increase of anticonvulsant action, partly in a decrease, and partly the pretreatment had no effect on the electroconvulsive threshold. The anticonvulsant effect of phenytoin was antagonized dose-dependently by naloxone, that of phenobarbital by the dose of 10 mg/kg of clocinnamox. A common denominator of the mu-antagonistic interactions with anticonvulsants cannot be found and the effects observed are therefore considered as "unspecific".

Studies on the involvement of dopamine D-1 and D-2 receptors in the anticonvulsant effect of dopamine agonists in various rodent models of epilepsy

Dopamine agonists with different selectivity for dopamine D-1 and D-2 receptors in the brain were tested for their effects: on thresholds for maximal electroshock seizures in mice and rats and for pentylenetetrazol-induced clonic seizures in mice; on seizures induced by air blast stimulation in gerbils, and on seizures induced by amygdala-kindling in rats. The mixed D-1/D-2 agonist apomorphine exerted anticonvulsant effects in all models except kindling. In gerbils and mice, the anticonvulsant action of apomorphine could be antagonized by the D-2 selective dopamine antagonist sulpiride. When injected alone, sulpiride exerted no significant effect on seizure activity. The preferential D-2 receptor agonists lisuride and (+)-PHNO ((+)-4-propyl-9-hydroxynaphthoxazine) differed in their profile of action. Both compounds displayed anticonvulsant efficacy in gerbils, while only lisuride proved capable of reducing kindled seizure severity. (+)-PHNO increased the threshold for electroconvulsions in mice while lisuride was ineffective in this respect or even decreased the threshold. The reverse was obtained in regard to electroshock seizures in rats. The threshold for seizures induced by pentylenetetrazol in mice was increased significantly by lisuride but not by (+)-PHNO. The selective dopamine D-1 receptor agonist SKF 38393-A exerted no anticonvulsant effect in any seizure test except a moderate increase of the electroconvulsive threshold in mice. In contrast, the dopamine precursor L-DOPA (injected after pretreatment with carbidopa) proved capable of reducing seizure activity in all models. In mice, the increase in the threshold for maximal electroshock seizures induced by L-DOPA was significantly reduced by sulpiride, which also attenuated the anticonvulsant effect of L-DOPA in gerbils. Collectively, the data indicate that dopamine D-2 receptors mediate the anticonvulsant effect of dopamine agonists and, at least in part, of L-DOPA whereas D-1 receptors seem not to be involved.

A TRH analog (DN-1417). Antagonistic effects on reserpine-induced decreases in local cerebral glucose utilization and cerebral monoamine levels

Thyrotropin-releasing hormone (TRH) and its analog, DN-1417 (gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate), significantly antagonized against reserpine-induced reduction of the spontaneous motor activity and the electroconvulsive threshold in mice. To search for sites of action and mechanisms, effects of DN-1417 on reserpine in local cerebral glucose utilization (LCGU) and cerebral monoamine levels were also investigated in rats. Reserpine (2 mg/kg, i.p., 24 hr pretreatment) reduced LCGU and the levels of cerebral monoamine in all the brain regions. DN-1417 (5 mg/kg, i.v.) significantly reversed the reduction of LCGU induced by reserpine in the thalamus dorsomedial nucleus, mamillary body, septal nucleus, caudate-putamen and nucleus accumbens. The effects of DN-1417 were completely abolished by pretreatment with a dopaminergic (DA) and a serotonergic (5-HT) receptor blocker, pimozide (1 mg/kg) and methysergide (5 mg/kg), respectively. DN-1417 (20 mg/kg, i.p.) reversed 5-HT level in the hypothalamus depleted by reserpine. These results suggest that the antagonistic effects of DN-1417 against reserpine-induced reduction of the locomotor activity and the electroconvulsive threshold seem to be mediated by DA- and 5-HT-ergic activations mainly in the nucleus accumbens and hypothalamus, respectively.

Correlation between alterations in brain GABA metabolism and seizure excitability following administration of GABA aminotransferase inhibitors and valproic acid—a re-evaluation

The time course of the effects of aminooxyacetic acid, ?-vinyl GABA, ?-acetylenic GABA, gabaculine, ethanolamine-O-sulphate (EOS) and valproic acid (VPA) on brain GABA content and the activities of glutamic acid decarboxylase (GAD) and GABA aminotransferase (GABA-T), the enzymes involved in biosynthesis and degradation of GABA, was re-determined and compared with the action on the electroconvulsive threshold in mice. All drugs caused significant increases in the seizure threshold, and the temporal pattern of this effect correlated rather well with the induced elevation of brain GABA. However, no clear relationship was found between the extent of GABA increase and the relative increase of seizure threshold. Except for VPA, the time course of the increment in brain GABA followed closely the inhibition of GABA-T. The activity of GAD was gradually decreased by ?-acetylenic GABA and a slow decline of GAD activity was also observed after ?-vinyl GABA. EOS and gabaculine suggesting a feedback repression of GAD synthesis by highly elevated GABA concentrations. Concomitant with significant reduction of GAD activity, a decrease in seizure threshold occurred though brain GABA levels remained markedly elevated. On the other hand, following administration of VPA the effect of GABA levels was paralleled by an increase in GAD activity indicating that the GABA-elevating action of this drug can be attributed at least in part to an activation of GABA synthesis. The data suggest that reduction of GAD activity may be an inevitable consequence of increasing brain GABA concentrations over a certain extent and this effect seems to limit the anticonvulsant efficacy of GABA-T inhibitors.