RESUMO
Absence epilepsy is generated by the cortico-thalamo-cortical network, which undergoes a finely tuned regulation by metabotropic glutamate (mGlu) receptors. We have shown previously that potentiation of mGlu1 receptors reduces spontaneous occurring spike and wave discharges (SWDs) in the WAG/Rij rat model of absence epilepsy, whereas activation of mGlu2/3 and mGlu4 receptors produces the opposite effect. Here, we have extended the study to mGlu5 receptors, which are known to be highly expressed within the cortico-thalamo-cortical network. We used presymptomatic and symptomatic WAG/Rij rats and aged-matched ACI rats. WAG/Rij rats showed a reduction in the mGlu5 receptor protein levels and in the mGlu5-receptor mediated stimulation of polyphosphoinositide hydrolysis in the ventrobasal thalamus, whereas the expression of mGlu5 receptors was increased in the somatosensory cortex. Interestingly, these changes preceded the onset of the epileptic phenotype, being already visible in pre-symptomatic WAG/Rij rats. SWDs in symptomatic WAG/Rij rats were not influenced by pharmacological blockade of mGlu5 receptors with MTEP (10 or 30 mg/kg, i.p.), but were significantly decreased by mGlu5 receptor potentiation with the novel enhancer, VU0360172 (3 or 10 mg/kg, s.c.), without affecting motor behaviour. The effect of VU0360172 was prevented by co-treatment with MTEP. These findings suggest that changes in mGlu5 receptors might lie at the core of the absence-seizure prone phenotype of WAG/Rij rats, and that mGlu5 receptor enhancers are potential candidates to the treatment of absence epilepsy. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
Assuntos
Epilepsia Tipo Ausência/tratamento farmacológico , Agonistas de Aminoácidos Excitatórios/uso terapêutico , Niacinamida/análogos & derivados , Receptores de Glutamato Metabotrópico/metabolismo , Fatores Etários , Animais , Ondas Encefálicas/efeitos dos fármacos , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Eletroencefalografia/métodos , Epilepsia Tipo Ausência/metabolismo , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hidrólise , Masculino , Atividade Motora/efeitos dos fármacos , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Fosfatos de Fosfatidilinositol/metabolismo , Piridinas/farmacologia , Ratos , Ratos Endogâmicos , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Córtex Somatossensorial/metabolismo , Tiazóis/farmacologia , Núcleos Ventrais do Tálamo/metabolismoRESUMO
Eight-month old WAG/Rij rats, which developed spontaneous occurring absence seizures, showed a reduced function of mGlu1 metabotropic glutamate receptors in the thalamus, as assessed by in vivo measurements of DHPG-stimulated polyphosphoinositide hydrolysis, in the presence of the mGlu5 antagonist MPEP as compared to age-matched non-epileptic control rats. These symptomatic 8-month old WAG/Rij rats also showed lower levels of thalamic mGlu1α receptors than age-matched controls and 2-month old (pre-symptomatic) WAG/Rij rats, as detected by immunoblotting. Immunohistochemical and in situ hybridization analysis indicated that the reduced expression of mGlu1 receptors found in symptomatic WAG/Rij rats was confined to an area of the thalamus that excluded the ventroposterolateral nucleus. No mGlu1 receptor mRNA was detected in the reticular thalamic nucleus. Pharmacological manipulation of mGlu1 receptors had a strong impact on absence seizures in WAG/Rij rats. Systemic treatment with the mGlu1 receptor enhancer SYN119, corresponding to compound RO0711401, reduced spontaneous spike and wave discharges spike-wave discharges (SWDs) in epileptic rats. Subcutaneous doses of 10 mg/kg of SYN119 only reduced the incidence of SWDs, whereas higher doses (30 mg/kg) also reduced the mean duration of SWDs. In contrast, treatment with the non-competitive mGlu1 receptor antagonist, JNJ16259685 (2.5 and 5 mg/kg, i.p.) increased the incidence of SWDs. These data suggest that absence epilepsy might be associated with a reduction of mGlu1 receptors in the thalamus, and that compounds that amplify the activity of mGlu1 receptors might be developed as novel anti-absence drugs. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
Assuntos
Epilepsia Tipo Ausência/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Regulação Alostérica , Animais , Ciprofloxacina/análogos & derivados , Ciprofloxacina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eletroencefalografia/efeitos dos fármacos , Epilepsia Tipo Ausência/tratamento farmacológico , Epilepsia Tipo Ausência/genética , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Inibidores da Síntese de Ácido Nucleico/farmacologia , Quinolinas/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos ACI , Ratos Endogâmicos , Receptores de Glutamato Metabotrópico/genética , Transdução de Sinais/efeitos dos fármacos , Núcleos Talâmicos/metabolismo , Núcleos Talâmicos/fisiopatologia , Tálamo/metabolismo , Tálamo/fisiopatologiaRESUMO
In the first experiment, the relationship between the phase of the estrous cycle and the number of spontaneously occurring spike-wave discharges was investigated in WAG/Rij rats, a model for generalized absence epilepsy. The electroencephalogram (EEG) was continuously recorded for 96 h in eight rats chronically equipped with cortical EEG electrodes. A circadian pattern emerged for the number of spike-wave discharges: a nadir during the first hours of the light period, and an acrophase during the first hours of the dark period. This daily maximum was increased at proestrus day compared with the other days of the cycle, when the plasma level of progesterone is enhanced specifically at these hours of this day. This suggests that progesterone enhances spike-wave discharges. There was no difference in the first few hours of the light period in the number of spike-wave discharges between proestrus and the three other days, suggesting that estradiol has no effect on spike-wave discharges. In the second study, the effects of the systemic administration of progesterone and 17 beta-estradiol on spike-wave discharges and spontaneous behavior were investigated. It was shown that progesterone (20 and 30 mg/kg) but not estradiol (0.17-1.5 mg/kg) increased the number and total duration of spike-wave discharges. On the other hand, injection of RU 38486 (10 and 30 mg/kg), an antagonist of intracellular progesterone receptors, had no effect on spike-wave discharges and did not block the stimulatory effect of progesterone. The antagonist of 17 beta-estradiol tamoxifen (1 and 3 mg/kg) did not evoke alterations in the number or duration of spike-wave discharges. Our results indicate that progesterone aggravates spike-wave discharges, but is not mediated through intracellular receptors. Since progesterone is rapidly metabolized in the brain to the positive modulator of GABA(A) receptor allopregnanolone, which increases spike-wave discharges in WAG/Rij rats, it is possible that the epileptiformic effects of progesterone are mediated through this metabolite.
Assuntos
Modelos Animais de Doenças , Eletroencefalografia/efeitos dos fármacos , Epilepsia Tipo Ausência/genética , Estradiol/farmacologia , Antagonistas de Hormônios/farmacologia , Ovário/fisiologia , Progesterona/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/genética , Epilepsia Tipo Ausência/psicologia , Ciclo Estral/efeitos dos fármacos , Ciclo Estral/genética , Feminino , Hormônios Esteroides Gonadais/fisiologia , Mifepristona/farmacologia , Ratos , Ratos EndogâmicosRESUMO
In the P(50) gating or conditioning-testing paradigm in the rat, two identical click stimuli are presented with an inter-click interval of 500 ms. The reaction towards the second click, as measured with evoked potentials, is reduced in respect to that towards the first click; this phenomenon is called sensory gating. In the present experiments, the inter-click interval was varied systematically and auditory evoked potentials were measured. Sensory gating was found to occur only at intervals between 500 and 1000 ms, but not at longer intervals. Fos immunohistochemistry was then performed using two groups of rats exposed to double clicks: the inter-click interval was 500 ms in the experimental group and 2500 ms in the control group. Fos induction was analyzed in selected brain structures. In the auditory pathways, Fos-immunoreactive neurons were found in both groups of rats in the inferior colliculus and medial geniculate body. Fos-immunoreactive cells were also examined in the septum and hippocampus. In the ventral part of the lateral septal nucleus, the labeled neurons were significantly fewer in the experimental animals compared to the control group. Smaller and non-significant quantitative differences of Fos-positive neurons were documented in the medial septum and hippocampal CA1 region. These data point out a selective decrease in the lateral septum of Fos induced by auditory sensory gating, and suggest an involvement of this structure, and possibly of other parts of the septo-hippocampal system, in sensory gating mechanisms. The results might be relevant for theories on sensory gating deficits in schizophrenia.