[Research advances in molecular genetics of epilepsies]. / Postepy w badaniach nad genetyka molekularna padaczek.

Last years brought a large number of papers shedding light on the molecular and genetic background of epilepsy. The aim of the present work was to review recent literature concerning this issue. In the first section, the authors presented biochemical and functional characteristics of receptors and ion channels. Mutations in their genes can lead to epileptic seizure development. Particularly, the role of GABA receptors as well as voltage-gated sodium, calcium and potassium channels in epilepsy pathogenesis was discussed. The second part of the work focuses on clinical implications of these receptors and channels disturbances. Epileptic syndromes with proved genetic defect are presented on the basis of recent literature and OMIM (Online Mendelian Inheritance in Man) database. The authors point out that reviewed results show vast heterogeneity of many known epileptic syndromes. On the other hand, defects in the same locus can result in heterogeneous phenotypes. This can indicate multifactorial pathogenesis of epilepsy and implicate further revision of epilepsies and epileptic seizures classification.

Differential effects of chronic haloperidol and clozapine administration on glutamatergic transmission in the fronto-parietal cortex in rats: microdialysis and electrophysiological studies.

Glutamatergic neurotransmission has been suggested to be involved in the pathogenesis of schizophrenia. Hence the aim of the present study was to examine the influence of haloperidol, a typical neuroleptic, and clozapine, an atypical one, on glutamatergic transmission in the fronto-parietal cortex. Haloperidol (1 mg/kg per day), or clozapine (30 mg/kg per day), was administered in drinking water for 6 weeks and was afterwards withdrawn for 4 days. The basal and the veratridine (100 microM)-induced extracellular glutamate and aspartate levels were measured by a microdialysis in vivo; neuronal discharges which developed in a Mg(2+)-free medium were recorded extracellularly in cortical slices ex vivo. Haloperidol elevated the basal, but not the veratridine-stimulated, extracellular levels of glutamate and aspartate. Haloperidol enhanced the activity of cortical neurons, which resulted in a decrease in the inhibitory influence of CGP 37849 on their frequency. The increased frequency of discharges induced by NMDA was not affected by haloperidol. In contrast, clozapine lowered both the basal and the stimulated levels of glutamate and aspartate, but had no effect on the activity of cortical neurons. The present study suggests that the two representatives of typical and atypical neuroleptics affect differently glutamatergic neurotransmission in the fronto-parietal cortex, which may reflect their diverse efficacy as antipsychotic agents.

Prolonged corticosterone treatment alters the responsiveness of 5-HT1A receptors to 8-OH-DPAT in rat CA1 hippocampal neurons.

Hippocampal 5-HT(1A) receptors have been shown to be suppressed by glucocorticoids in a variety of animal studies, however the molecular mechanism and the functional meaning of this effect are still not well understood. The present study was designed to investigate the impact of repeated administration of corticosterone (10 mg/kg s.c. twice daily for 7 days) on the functional consequences of 5-HT(1A) receptor stimulation measured electrophysiologically in hippocampal slices. Additionally, the effects of corticosterone on 5-HT(1A) receptor binding and on receptor mRNA levels in the hippocampus were studied. Prolonged, but not acute treatment with corticosterone attenuated (+/-)-8-hydroxy-2-di- N-propylamino)tetralin hydrobromide (8-OH-DPAT)-induced inhibition of population spikes, and 8-OH-DPAT-induced hyperpolarization in rat CA1 hippocampal neurons. Chronic, but not acute treatment with corticosterone also decreased 5-HT(1A) receptor binding in the CA1 region (in the ventral part only) and the dentate gyrus. A single dose of corticosterone increased [(3)H]8-OHDPAT binding in the dentate gyrus and in the CA3 and CA4 hippocampal regions. Only acute, but not prolonged treatment with corticosterone decreased the level of 5-HT(1A) receptor mRNA in the CA1 region and dentate gyrus of the hippocampus. 5-HT turnover in the hippocampus was not influenced by chronic corticosterone. It is concluded that a chronically elevated level of corticosterone can induce functional desensitization of 5-HT(1A) receptors in the CA1 area of the hippocampus, although this effect is not always followed consequently by decreases in 5-HT(1A) receptor synthesis in this or other areas of the hippocampus.

Group II mGlu receptor agonists inhibit behavioural and electrophysiological effects of DOI in mice.

It has been suggested that metabotropic glutamate (mGlu) receptor agonists selective for Group II mGlu receptors may have antipsychotic action. Therefore, we studied whether the effects, which could be related to psychotomimetic action of hallucinogenic drugs, are inhibited by Group II mGlu receptor agonists. The selective mGlu2/3 agonists LY354740 and LY379268 inhibited (+/-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head twitches in mice in a dose-dependent manner. Furthermore, LY379268 suppressed an increase in the frequency of spontaneous excitatory synaptic potentials induced by bath-applied DOI in layer V pyramidal cells recorded in the murine medial frontal cortex. The data indicate that Group II mGlu receptor agonists may counteract the effects of hallucinogenic drugs.

Differential effects of repeated imipramine on hippocampal responsiveness to adenosine and serotonin.

Imipramine-induced enhancement of the inhibitory action of 5-HT(lA) receptor activation in hippocampal pyramidal neurons has been attributed to alterations in the transduction mechanism that involves G protein-dependent opening of K(+) channels. Postsynaptic 5-HT(lA) and adenosine Al receptors may share that transduction pathway. We investigated the influence of repeated imipramine administration on 5-HT(lA) and adenosine A1 receptor-mediated effects in rat hippocampal slices. Repeated imipramine selectively enhanced the postsynaptic effects of 5-HT(1A) receptor activation, including hyperpolarization and reduction of input resistance of neurons and reduction of the population spike amplitude. In contrast, after imipramine treatment only the presynaptic effect of adenosine receptor agonists, a decrease of the field excitatory postsynaptic potential, was enhanced. The data demonstrate that alterations in the presumed common transduction mechanism that was postulated for the 5-HT(lA) and adenosine A1 receptor-mediated activation of K(+) channels are not involved in the effect of repeated imipramine administration.

Imipramine but not 5-HT(1A) receptor agonists or neuroleptics induces adaptive changes in hippocampal 5-HT(1A) and 5-HT(4) receptors.

It has been reported that the treatment with a tricyclic antidepressant imipramine induces an increase in the sensitivity of 5-HT(1A) receptors and a decrease in the sensitivity of 5-HT(4) receptors in the rat hippocampus. 5-HT(1A) receptor agonists and neuroleptics also affect 5-HT(1A) receptors in different brain areas; therefore, it was of interest to compare their effects on hippocampal 5-HT receptors with the influence of the well-established antidepressant imipramine. We studied the effects of repeated treatment with imipramine, the 5-HT(1A) receptor agonists 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone, and the neuroleptics haloperidol and clozapine on the sensitivity of rat hippocampal CA1 neurons to 5-HT(1A)- and 5-HT(4) receptor activation. Imipramine was administered for 21 days (10 mg/kg p.o., twice daily), 8-OH-DPAT for 7 days (1 mg/kg s.c., twice daily) and buspirone for 21 days (5 mg/kg s.c., twice daily). The rats received haloperidol (1 mg/kg) and clozapine (30 mg/kg) for 6 weeks in drinking water. Hippocampal slices were prepared 2 days after the last treatment with imipramine, 8-OH-DPAT or buspirone, and 5 days after the last treatment with the neuroleptics. Using an extracellular in vitro recording, we studied changes in the amplitude of stimulation-evoked population spikes, induced by 5-HT, 8-OH-DPAT and the 5-HT(4) receptor agonist zacopride. Activation of 5-HT(1A) receptors decreased, while activation of 5-HT(4) receptors increased the amplitude of population spikes. Imipramine significantly enhanced the inhibitory effects of 5-HT and 8-OH-DPAT, and attenuated the excitatory effect of zacopride. No other treatment used in the present study changed the sensitivity of hippocampal CA1 neurons to 5-HT(1A) and 5-HT(4) receptors activation. These findings indicate that adaptive changes in the sensitivity of hippocampal neurons to 5-HT(1A) and 5-HT(4) receptors agonists are specific to imipramine and may thus-at least partly-mediate its effects.