Behavioral analysis of rats susceptible and non-susceptible to clonic convulsions induced by DMCM, a benzodiazepine inverse agonist

Há evidências clínicas e farmacológicas que sugerem uma deficiência na neurotransmissão GABAérgica, mediada pelo receptor GABAR/BZD, nas epilepsias e nas desordens psiquiátricas das ansiedades e das depressões. O objetivo deste trabalho foi verificar se ratos que diferem quanto à sensibilidade às convulsões clônicas provocadas pelo DMCM, um agonista inverso benzodiazepínico, também se diferenciariam em testes comportamentais utilizados para estudos de ansiedade e depressão. Ratos Wistar, machos, adultos, foram injetados intraperitonialmente, uma vez (primeiro experimento) ou duas vezes (segundo experimento), com uma dose de DMCM que produz convulsões clônicas em 50 por cento dos ratos injetados. A partir destes procedimentos, foram separados, em cada um dos experimentos, dois grupos distintos: o grupo susceptível (SC), constituído de ratos que apresentaram convulsões clônicas na única exposição (primeiro experimento) ou em ambas as exposições (segundo experimento); e o grupo não susceptível (NSC), composto por ratos que não apresentaram sinais de convulsão na única exposição (primeiro experimento) ou em ambas as exposições (segundo experimento). Após 20 dias da única exposição ao DMCM (primeiro experimento) ou da segunda exposição ao DMCM (segundo experimento), os animais foram expostos aos seus respectivos testes comportamentais. Diferentes grupos de ratos foram usados em cada um dos modelos comporta mentais, com a exceção dos ratos do segundo experimento que foram expostos ao labirinto em cruz elevado, e que, após 20 dias, foram expostos ao campo aberto. Os resultados obtidos no primeiro experimento demonstraram não haver diferenças estatísticas entre os grupos SC e NSC nos modelos comportamentais utilizados. Entretanto, no segundo experimento , o grupo SC apresentou um menor tempo de permanência nos braços abertos do labirinto em cruz elevado, o que indica um nível mais alto de ansiedade, e no campo aberto, este grupo apresentou uma maior freqüência de "rearing", comparado com o grupo NSC. Na natação forçada não foram observadas diferenças comportamentais entre os grupos. Concluindo, estes resultados sugerem a existência de uma relação neurobiológica, no que se refere ao complexo ionotrópico GABAR/BZD, entre as epilepsias e as ansiedades, bem como a inexistência desta relação entre as epilepsias e as depressõesBV UNIFESP: Teses e dissertaçõe

Rewarding and antidepressant properties of ketamine and ethanol: effects on the BDNF and TrkB and p75NTR receptors

There is a high level of comorbidity between depression and alcohol use disorder. Subanesthetic doses of ketamine induce short-acting and enduring antidepressant effects after a single or a few administrations. Considering such comorbidity, we assessed, in Swiss male mice, if ketamine-induced antidepressant-like effects would alter ethanol's rewarding effects; and, if ethanol pretreatment would alter the rewarding and antidepressant effects of ketamine. The role of the brain-derived neurotrophic factor (BDNF) and its high and low affinity receptors TrkB and p75NTR, respectively, in both reward and depression-related behaviors is well established. The present study assessed, in outbred Swiss male mice, the expression of these proteins in the prefrontal cortex and hippocampus. Ketamine did not alter the development of ethanol-induced conditioned place preference (CPP), yet ethanol inhibited the expression of CPP induced by 50 mg/kg ketamine. The antidepressant action of 50 mg/kg ketamine was attenuated after repeated treatment (i.e., developed tolerance), an effect blocked by ethanol preexposure; ethanol also inhibited the antidepressant effect of 30 mg/kg ketamine. Ketamine (50 mg/kg) and Ethanol–Ketamine (50 mg/kg) groups showed lower levels of 145 kDa TrkB in the hippocampus than Saline-treated group. Ethanol–Ketamine (50 mg/kg) decreased the hippocampal expression of p75NTR compared to Saline–Saline and Saline–Ethanol groups. Ketamine (50 mg/kg) induced hippocampal downregulation of 145 kDa TrkB may contribute to ketamine-induced antidepressant tolerance. Likewise, a relationship between low hippocampal levels of p75NTR in the Ethanol–Ketamine (50 mg/kg) and ketamine-induced CPP blockade may be considered. The findings underscore potential ethanol–ketamine interactions likely to undermine ketamine putative antidepressant effects.Fil: Contó, Marcos Brandão. Universidade de Sao Paulo; BrasilFil: Pautassi, Ricardo Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Camarini, Rosana. Universidade de Sao Paulo; Brasi

Behavioral differences between subgroups of rats with high and low threshold to clonic convulsions induced by DMCM, a benzodiazepine inverse agonist

In epileptic patients, there is a high incidence of psychiatric comorbidities, such as anxiety. Gamma-aminobutyric acid (GABA) ionotropic receptor GABA(A)/benzodiazepine allosteric site is involved in both epilepsy and anxiety. This involvement is based on the fact that benzodiazepine allosteric site agonists are anticonvulsant and anxiolytic drugs; on the other hand, benzodiazepine inverse agonists are potent convulsant and anxiogenic drugs. the aim of this work was to determine if subgroups of rats selected according to their susceptibility to clonic convulsions induced by a convulsant dose 50% (CD50) of DMCM, a benzodiazepine inverse agonist, would differ in behavioral tests commonly used to measure anxiety (elevated plus-maze, open field) and depression (forced swimming test). in the first experiment, subgroups of adult male Wistar rats were selected after a single dose of DMCM and in the second experiment they were selected after two injections of DMCM given after an interval of 1 week. Those rats presenting full clonic convulsions were termed Low Threshold rats to DMCM-induced clonic convulsions (LTR) and those not having clonic convulsions High Threshold rats to DMCM-induced clonic convulsions (HTR). in both experiments, only those rats presenting full clonic convulsions induced by DMCM and those not showing any signs of motor disturbances were used in the behavioral tests. the results showed that the LTR subgroup selected after two injections of a CD50 of DMCM spent a significantly lower time in the open arms of the elevated plus-maze and in the off the walls area of the open field; moreover, this group also presented a higher number of rearings in the open field. There were no significant differences between HTR and LTR subgroups in the forced swimming test. LTR and HTR subgroups selected after only one injection of DMCM did not differ in the three behavioral tests. To verify if the behavioral differences between HTR and LTR subgroups of rats selected after two injections of DMCM were due to the clonic convulsion, another experiment was carried out in which subgroups of rats susceptible and nonsusceptible to clonic convulsions induced by a CD50 of picrotoxin, a GABA(A) receptor channel blocker, were selected and submitted to the elevated plus-maze and open field tests. the results obtained did not show any significant differences between these two subgroups in the elevated plus-maze and open field tests. in another approach to determine the relation between fear/anxiety and susceptibility to clonic convulsions, subgroups of rats were selected in the elevated plus-maze as more or less fearful/anxious. the CD50 for clonic convulsions induced by DMCM was determined for each of these two subgroups. the results showed a significantly lower CD50 for the more fearful/anxious subgroup, which means a higher susceptibility to clonic convulsions induced by DMCM. the present findings show a relation between susceptibility to clonic convulsions and fear/anxiety and vice versa which may be due to differences in the assembly of GABA(A)/allosteric benzodiazepine site receptors in regions of the brain. (c) 2005 Elsevier Inc. All rights reserved.Universidade Federal de São Paulo, Dept Psicobiol, Escola Paulista Med, BR-0402390 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psicobiol, Escola Paulista Med, BR-0402390 São Paulo, BrazilWeb of Scienc

Relationship between thresholds to convulsions induced by a benzodiazepine inverse agonist and [H-3]-L-glutamate binding in the membranes of brain regions

Although some studies have investigated the influence of kindling model of epilepsy on the glutamatergic neurotransmission, the relation between glutamatergic receptors and seizure susceptibility remains unclear. the present study sought to determine if rats with high (HTR) and low (LTR) thresholds to clonic convulsions induced by the benzodiazepine inverse agonist DMCM differed in the [H-3]-l-glutamate binding to membranes from discrete brain regions. Compared to the HTR subgroup, the LTR subgroup presented a lower binding of [H-3]-l-glutamate in the hippocampus, frontal cortex and amygdala plus limbic cortex, suggesting that glutamatergic receptors in these brain regions may underlie the susceptibility to DMCM-induced convulsions.Associacao Fundo de Incentivo a Pesquisa (AFIP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Universidade Federal de São Paulo, Dept Psicobiol, Escola Paulista Med UNIFESP EPM, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psicobiol, Escola Paulista Med UNIFESP EPM, BR-04023062 São Paulo, BrazilWeb of Scienc