EXPERIMENTAL EMOTIONAL DISORDERS IN EPILEPSY AND THE IMPLICATION OF MUSCARINIC ACETYLCHOLINE RECEPTORS: A FORGOTTEN PUTATIVE THERAPEUTIC TARGET

Over the last decades it has been observed a major breakthrough in the development of new drugs in the treatment of emotional disorders. Despite this evolutionary framework, the neurobiological mechanisms involved in anxiety process are poorly understood and new approaches are still required, taking into account the resistance to therapies and therapeutic side-effects. Despite the clear involvement of muscarinic acetylcholine receptors (mAChR) in the modulation of synaptic transmission and its role in controlling experimental epileptogenesis and emotional outcomes, little attention has been paid to this neurotransmitter system and its feasible action in the treatment of pathological processes. In this sense, the present review aims to shed light on this important, but not deeply explored receptor system in the control of experimental epilepsy and anxiety, besides discussing its implementation in translational studies

Quantitative changes of nicotinic receptors in the hippocampus of dystrophin-deficient mice

Lack of dystrophin in Duchenne muscle dystrophy (DMD) and in the mutant mdx mouse results in progressive muscle degeneration, structural changes at the neuromuscular junction, and destabilization of the nicotinic acetylcholine receptors (nAChRs). One-third of DMD patients also present non-progressive cognitive impairments. Considering the role of the cholinergic system in cognitive functions, the number of nAChR binding sites and the mRNA levels of alpha 4, beta 2, and alpha 7 subunits were determined in brain regions normally enriched in dystrophin (cortex, hippocampus and cerebellum) of mdx mice using specific ligands and reverse-transcription polymerase chain reaction assays, respectively. Membrane preparations of these brain regions were obtained from male control and mdx mice at 4 and 12 months of age. the number of [H-3]-cytisine (alpha 4 beta 2) and [I-125]-alpha-bungarotoxin ([I-125]-alpha BGT, alpha 7) binding sites in the cortex and cerebellum was not altered with age or among age-matched control and mdx mice. A significant reduction in [H-3]-cytisine (48%) and [I-125]-alpha BGT (37%) binding sites was detected in the hippocampus of mdx mice at 12 months of age. When compared with the age-matched control groups, the mdx mice did not have significantly altered [H-3]-cytisine binding in the hippocampus, but [I-125]-alpha BGT binding in the same brain region was 52% higher at 4 months and 20% lower at 12 months. mRNA transcripts for the nAChR alpha 4, beta 2, and alpha 7 subunits were not significantly altered in the same brain regions of all animal groups. These results suggest a potential alteration of the nicotinic cholinergic function in the hippocampus of dystrophin-deficient mice, which might contribute to the impairments in cognitive functions, such as learning and memory, that have been reported in the dystrophic murine model and DMD patients. (C) 2012 Elsevier B.V. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo, Escola Paulista Med, Sect Nat Prod, Dept Pharmacol, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Sect Expt Endocrinol, Dept Pharmacol, São Paulo, BrazilUniv Fed Santa Catarina, Dept Pharmacol, Neuropharmacol Lab, Florianopolis, SC, BrazilAmazon Biotechnol Ctr, Lab Pharmacol & Toxicol, Manaus, AM, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Sect Nat Prod, Dept Pharmacol, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Sect Expt Endocrinol, Dept Pharmacol, São Paulo, BrazilWeb of Scienc

Estresse e convulsões: participação dos opioides endogenos

Tese (doutorado) - Universidade de São Paulo. Departamento de Fisiologia e Biofisic

Distinctive stress sensitivity and anxiety-like behavior in female mice: Strain differences matter

Epidemiologic studies have shown that the prevalence of stress-related mood disorders is higher in women, which suggests a different response of neuroendocrine circuits involved in the response to stressful events, as well as a genetic background influence. The aim of this study was to investigate the baseline differences in anxiety-like behaviors of females of two commonly used mice strains. Secondly, we have also aimed to study their behavioral and biochemical alterations following stress. Naïve 3-4 months-old Swiss and C57BL/6 female mice were evaluated in the elevated plus maze (EPM) and in the acoustic startle response (ASR) for anxiety-like behaviors. Besides, an independent group of animals from each strain was exposed to cold-restraint stress (30 min/4 °C, daily) for 21 consecutive days and then evaluated in EPM and in the sucrose consumption tests. Twenty-four hours following behavioral experimentation mice were decapitated and their hippocampi (HP) and cortex (CT) dissected for further Western blotting analysis of glucocorticoid receptor (GR) and glial fibrillary acid protein (GFAP). Subsequent to each behavioral protocol, animal blood samples were collected for further plasma corticosterone analysis. C57BL/6 presented a lower anxiety profile than Swiss female mice in both behavioral tests, EPM and ASR. These phenomena could be correlated with the fact that both strains have distinct corticosterone levels and GR expression in the HP at the baseline level. Moreover, C57BL/6 female mice were more vulnerable to the stress protocol, which was able to induce an anhedonic state characterized by lower preference for a sucrose solution. Behavioral anhedonic-like alterations in these animals coincide with reduced plasma corticosterone accompanied with increased GR and GFAP levels, both in the HP. Our data suggest that in C57BL/6 female mice a dysregulation of the hypothalamus-pituitary-adrenal axis (HPA-axis) occurs, in which corticosterone acting on GRs would possibly exert its pro-inflammatory role, ultimately leading to astrocyte activation in response to stress. Keywords: Stress-related disorders, Female mice, Anxiety-like behavior, Depression-like behavior, Neuroinflammation, Anhedoni

Short- and long-term anxiogenic effects induced by a single injection of subconvulsant doses of pilocarpine in rats: investigation of the putative role of hippocampal pathways

Behavioral consequences of convulsive episodes are well documented, but less attention was paid to changes that occur in response to subconvulsant doses of drugs. We investigated short- and long-term effects of a single systemic injection of a subconvulsant dose of pilocarpine on the behavior of rats as evaluated in the elevated plus maze. Pilocarpine induced an anxiogenic-like profile 24 h later, and this effect persisted for up to 3 months (% of time spent on open arms at 24 h, control = 35.47 +/- 3.23; pilocarpine 150 = 8.2 +/- 2.6; 3 months, control = 31.9 +/- 5.5; pilocarpine 150 = 9.3 +/- 4.9). Temporary inactivation of fimbria-fornix with lidocaine 4% promoted an anxiolytic-like effect per se, suggesting a tonic control of this pathway on the modulation of anxiety-related behaviors. Lidocaine also reduced the anxiogenic-like profile of animals tested 1 month after pilocarpine treatment (% of time spent on open arms, saline + phosphate-buffered saline (PBS) = 31.7 + 3.7; saline + lidocaine = 54.4 + 4.7; pilocarpine + PBS = 10.3 + 4.1; pilocarpine + lidocaine = 40.1 + 9.1). To determine whether the anxiogenic-like effect was mediated by septal region or by direct hippocampal projections to the diencephalon, the neural transmission of post-commissural fornix was blocked, and a similar reduction in the anxiogenic-like effect of pilocarpine was observed. Our findings suggest that a single systemic injection of pilocarpine may induce long-lasting anxiogenic-like behavior in rats, an effect that appears to be mediated, in part, through a direct path from hippocampus to medial hypothalamic sites involved in fear responses.Brazilian National Research Council (CNPq)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)CAPESCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)CNP

Quantitative changes of nicotinic receptors in the hippocampus of dystrophin-deficient mice

Lack of dystrophin in Duchenne muscle dystrophy (DMD) and in the mutant mdx mouse results in progressive muscle degeneration, structural changes at the neuromuscular junction, and destabilization of the nicotinic acetylcholine receptors (nAChRs). One-third of DMD patients also present non-progressive cognitive impairments. Considering the role of the cholinergic system in cognitive functions, the number of nAChR binding sites and the mRNA levels of alpha 4, beta 2, and alpha 7 subunits were determined in brain regions normally enriched in dystrophin (cortex, hippocampus and cerebellum) of mdx mice using specific ligands and reverse-transcription polymerase chain reaction assays, respectively. Membrane preparations of these brain regions were obtained from male control and mdx mice at 4 and 12 months of age. the number of [H-3]-cytisine (alpha 4 beta 2) and [I-125]-alpha-bungarotoxin ([I-125]-alpha BGT, alpha 7) binding sites in the cortex and cerebellum was not altered with age or among age-matched control and mdx mice. A significant reduction in [H-3]-cytisine (48%) and [I-125]-alpha BGT (37%) binding sites was detected in the hippocampus of mdx mice at 12 months of age. When compared with the age-matched control groups, the mdx mice did not have significantly altered [H-3]-cytisine binding in the hippocampus, but [I-125]-alpha BGT binding in the same brain region was 52% higher at 4 months and 20% lower at 12 months. mRNA transcripts for the nAChR alpha 4, beta 2, and alpha 7 subunits were not significantly altered in the same brain regions of all animal groups. These results suggest a potential alteration of the nicotinic cholinergic function in the hippocampus of dystrophin-deficient mice, which might contribute to the impairments in cognitive functions, such as learning and memory, that have been reported in the dystrophic murine model and DMD patients. (C) 2012 Elsevier B.V. All rights reserved