RESUMO
Under stressful conditions, the hypothalamic-pituitary-adrenal (HPA) axis acts to promote transitory physiological adaptations that are often resolved after the stressful stimulus is no longer present. In addition to corticosteroids (e.g., cortisol), the neurosteroid allopregnanolone (3α,5α-tetrahydroprogesterone, 3α-hydroxy-5α-pregnan-20-one) participates in negative feedback mechanisms that restore homeostasis. Chronic, repeated exposure to stress impairs the responsivity of the HPA axis and dampens allopregnanolone levels, participating in the etiopathology of psychiatric disorders, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). MDD and PTSD patients present abnormalities in the HPA axis regulation, such as altered cortisol levels or failure to suppress cortisol release in the dexamethasone suppression test. Herein, we review the neurophysiological role of allopregnanolone both as a potent and positive GABAergic neuromodulator but also in its capacity of inhibiting the HPA axis. The allopregnanolone function in the mechanisms that recapitulate stress-induced pathophysiology, including MDD and PTSD, and its potential as both a treatment target and as a biomarker for these disorders is discussed.
Assuntos
Transtorno Depressivo Maior/fisiopatologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Pregnanolona/fisiologia , Adaptação Fisiológica , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Doença Crônica , Corticosterona/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Retroalimentação Fisiológica , Feminino , Agonistas de Receptores de GABA-A/uso terapêutico , Humanos , Masculino , Modelos Biológicos , Pregnanolona/biossíntese , Receptores de GABA-A/fisiologia , Caracteres Sexuais , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Estresse Fisiológico , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologia , Ácido gama-Aminobutírico/fisiologiaRESUMO
Extrasynaptic α5 -subunit containing GABAA (α5 -GABAA ) receptors participate in chronic pain. Previously, we reported a sex difference in the action of α5 -GABAA receptors in dysfunctional pain. However, the underlying mechanisms remain unknown. The aim of this study was to examine this sexual dimorphism in neuropathic rodents and the mechanisms involved. Female and male Wistar rats or ICR mice were subjected to nerve injury followed by α5 -GABAA receptor inverse agonist intrathecal administration, L-655,708. The drug produced an antiallodynic effect in nerve-injured female rats and mice, and a lower effect in males. We hypothesized that changes in α5 -GABAA receptor, probably influenced by hormonal and epigenetic status, might underlie this sex difference. Thus, we performed qPCR and western blot. Nerve injury increased α5 -GABAA mRNA and protein in female dorsal root ganglia (DRG) and decreased them in DRG and spinal cord of males. To investigate the hormonal influence over α5 -GABAA receptor actions, we performed nerve injury to ovariectomized rats and reconstituted them with 17ß-estradiol (E2). Ovariectomy abrogated L-655,708 antiallodynic effect and E2 restored it. Ovariectomy decreased α5 -GABAA receptor and estrogen receptor α protein in DRG of neuropathic female rats, while E2 enhanced them. Since DNA methylation might contribute to α5 -GABAA receptor down-regulation in males, we examined CpG island DNA methylation of α5 -GABAA receptor coding gene through pyrosequencing. Nerve injury increased methylation in male, but not female rats. Pharmacological inhibition of DNA methyltransferases increased α5 -GABAA receptor and enabled L-655,708 antinociceptive effect in male rats. These results suggest that α5 -GABAA receptor is a suitable target to treat chronic pain in females.
Assuntos
Epigênese Genética/genética , Nociceptividade/fisiologia , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/fisiopatologia , Receptores de GABA-A/genética , Receptores de GABA-A/fisiologia , Animais , Metilação de DNA/genética , Estradiol/farmacologia , Feminino , Agonistas GABAérgicos/administração & dosagem , Agonistas GABAérgicos/farmacologia , Gânglios Espinais/metabolismo , Imidazóis/farmacologia , Injeções Espinhais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ovariectomia , Medição da Dor , Ratos , Ratos Wistar , Caracteres SexuaisRESUMO
Recently, we demonstrated the promising anxiolytic action of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) in mice. For this reason, the objective of this study was to expand our previous findings by investigating the contribution of serotoninergic and GABAergic systems to the anxiolytic action of this compound. Pretreatment with different serotoninergic antagonists (pindolol, WAY100635 and ketanserin) blocked the anxiolytic effect caused by 4-PSQ (50 mg/kg, per oral) in the elevated plus maze (EPM) test. The contribution of the GABAergic system was investigated by pretreatment with pentylenetetrazole (a GABAA receptor antagonist) (PTZ). 4-PSQ diminished the PTZ-induced anxiety, and did not modify the locomotor, exploratory and motor activities of mice. Later, this group of animals was euthanized and the blood was removed to determine the levels of corticosterone, and cerebral cortex and hippocampus to determine the mRNA expression levels of cAMP response element binding protein (CREB), brain derived neurotrophic factor (BDNF) and nuclear factor kappa B (NF-κB), as well as the Na+, K+ ATPase activity and reactive species (RS) levels. 4-PSQ was able to significantly reverse the increase in RS and corticosterone levels, as well as the decrease of CREB and BDNF expression in the cerebral structures and increase of NF-κB expression in the hippocampus. Finally, 4-PSQ restored the Na+, K+ ATPase activity in the cerebral structures evaluated. Here, we showed that the modulation of serotonergic and GABAergic systems, factors related to neurogenesis, oxidative status and Na+, K+ ATPase activity contributes to the anxiolytic effect of 4-PSQ and reinforces the therapeutical potential of this compound for the treatment of anxiety.
Assuntos
Ansiolíticos/administração & dosagem , Ansiedade/fisiopatologia , Quinolinas/administração & dosagem , Receptores de GABA-A/fisiologia , Selênio/administração & dosagem , Serotonina/fisiologia , Animais , Ansiedade/prevenção & controle , Antagonistas de Receptores de GABA-A/administração & dosagem , Masculino , Camundongos , Pindolol/administração & dosagem , Quinolinas/química , Receptores de GABA-A/administração & dosagem , Selênio/química , Antagonistas da Serotonina/administração & dosagemRESUMO
The sympathetic nervous system (SNS) regulates body functions in normal and pathological conditions and is characterized by the presence of a neuroplastic phenomenon, termed ganglionic long-term potentiation (gLTP). In hypertension, either in spontaneously hypertensive rats (SHR) or in humans, sympathetic hyperfunction, such as elevated SNS outflow and changes in synaptic plasticity have been described. Because enhanced SNS outflow is detected in the hypertensive stage and, more importantly, in the prehypertensive phase of SHR, here we explored whether synaptic plasticity, particularly gLTP, was modified in the superior cervical ganglia (SCG) of prehypertensive SHR. Furthermore, considering that GABA modulates sympathetic synaptic transmission and gLTP in Wistar rats, we studied whether GABA might modulate gLTP expression in SHR. We characterized gLTP in the SCG of young prehypertensive 6-week-old (wo) and adult hypertensive (12 wo) SHR and in the SCG of Wistar Kyoto (WKy) normotensive control rats of the same ages. We found that gLTP was expressed in 6 wo SHR, but not in 12 wo rats. By contrast, in WKy, gLTP was expressed in 12 wo, but not in 6 wo rats. We also found that gLTP depends on GABA modulation, as blockade of GABA-A subtype receptors with its antagonist bicuculline unmasked gLTP expression in adult SHR and young WKy. We propose that (1) activity-dependent changes in synaptic efficacy are altered not only during hypertension but also before its onset and (2) GABA may play a modulatory role in the changes in synaptic plasticity in SHR, because the blockade of GABA-A receptors unmasked the expression of gLTP. These early changes in neuroplasticity and GABA modulation of gLTP could be part of the sympathetic hyperfunction observed in hypertension.
Assuntos
Gânglios Simpáticos/fisiopatologia , Hipertensão/fisiopatologia , Potenciação de Longa Duração/fisiologia , Pré-Hipertensão/fisiopatologia , Ácido gama-Aminobutírico/fisiologia , Animais , Antagonistas de Receptores de GABA-A/farmacologia , Gânglios Simpáticos/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptores de GABA-A/fisiologia , Ácido gama-Aminobutírico/farmacologiaRESUMO
BACKGROUND: Decreased short-interval intracortical inhibition (SICI) to transcranial magnetic stimulation (TMS) of the primary motor cortex was described in subjects with restless legs syndrome/Willis-Ekbom disease (RLS/WED). It remained to be determined whether the magnitude of SICI decrease would be similar across levels of RLS/WED severity. Moreover, it was unknown whether, in addition to decreases in SICI, changes in cortical thickness or area could be detected in subjects with RLS/WED compared to controls. The objective of this study was to compare SICI, cortical thickness, and cortical area in subjects with idiopathic mild to moderate RLS/WED, severe to very severe RLS/WED, and controls. METHODS: The severity of RLS/WED was assessed by the International Restless Legs Syndrome Severity Scale (IRLSS). SICI and 3T magnetic resonance imaging (MRI) data of subjects with RLS/WED and controls were compared. A receiver operating characteristic curve for SICI was designed for discrimination of participants with RLS/WED from controls. Cortical thickness and area were assessed by automated surface-based analysis. RESULTS: SICI was significantly reduced in patients with mild to moderate and severe to very severe RLS/WED, compared to controls (one-way analysis of variance: F = 9.62, p < 0.001). Receiver operating characteristic curve analysis predicted RLS/WED when SICI was above 35% (area under the curve = 0.79, 95% CI 0.67-0.91, p < 0.001). Analyses of the whole brain and of regions of interest did not reveal differences in gray matter thickness or area between controls and subjects with RLS/WED. CONCLUSION: SICI is an accurate cortical biomarker that can support the diagnosis of RLS/WED even in subjects with mild symptoms, but cortical thickness and area were not useful for discriminating subjects with this condition from controls.
Assuntos
Encéfalo/diagnóstico por imagem , Córtex Motor/diagnóstico por imagem , Síndrome das Pernas Inquietas/terapia , Estimulação Magnética Transcraniana/efeitos adversos , Adulto , Encéfalo/fisiopatologia , Brasil/epidemiologia , Estudos de Casos e Controles , Excitabilidade Cortical , Potencial Evocado Motor , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Córtex Motor/fisiopatologia , Qualidade de Vida , Receptores de GABA-A/fisiologia , Síndrome das Pernas Inquietas/diagnóstico , Síndrome das Pernas Inquietas/fisiopatologia , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Estimulação Magnética Transcraniana/métodosRESUMO
Preservation of a balance between synaptic excitation and inhibition is critical for normal brain function. A number of homeostatic cellular mechanisms have been suggested to play a role in maintaining this balance, including long-term plasticity of GABAergic inhibitory synapses. Many previous studies have demonstrated a coupling of postsynaptic spiking with modification of perisomatic inhibition. Here, we demonstrate that activation of NMDA-type glutamate receptors leads to input-specific long-term potentiation of dendritic inhibition mediated by somatostatin-expressing interneurons. This form of plasticity is expressed postsynaptically and requires both CaMKIIα and the ß2 subunit of the GABA-A receptor. Importantly, this process may function to preserve dendritic inhibition, as genetic deletion of NMDAR signaling results in a selective weakening of dendritic inhibition. Overall, our results reveal a new mechanism for linking excitatory and inhibitory input in neuronal dendrites and provide novel insight into the homeostatic regulation of synaptic transmission in cortical circuits.
Assuntos
Dendritos/fisiologia , Potenciação de Longa Duração/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Inibição Neural/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Ácido gama-Aminobutírico/fisiologia , Animais , Sinalização do Cálcio/fisiologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Piramidais/fisiologia , Receptores de GABA-A/fisiologiaRESUMO
l-Cysteine is an endogenous sulfur-containing amino acid with multiple and varied roles in the central nervous system, including neuroprotection and the maintenance of the redox balance. However, it was also suggested as an excitotoxic agent implicated in the pathogenesis of neurological disorders such as Parkinson's and Alzheimer's disease. l-Cysteine can modulate the activity of ionic channels, including voltage-gated calcium channels and glutamatergic NMDA receptors, whereas its effects on GABAergic neurotransmission had not been studied before. In the present work, we analyzed the effects of l-cysteine on responses mediated by homomeric GABAA ρ1 receptors, which are known for mediating tonic γ-aminobutyric acid (GABA) responses in retinal neurons. GABAA ρ1 receptors were expressed in Xenopus laevis oocytes and GABA-evoked chloride currents recorded by two-electrode voltage-clamp in the presence or absence of l-cysteine. l-Cysteine antagonized GABAA ρ1 receptor-mediated responses; inhibition was dose-dependent, reversible, voltage independent, and susceptible to GABA concentration. Concentration-response curves for GABA were shifted to the right in the presence of l-cysteine without a substantial change in the maximal response. l-Cysteine inhibition was insensitive to chemical protection of the sulfhydryl groups of the ρ1 subunits by the irreversible alkylating agent N-ethyl maleimide. Our results suggest that redox modulation is not involved during l-cysteine actions and that l-cysteine might be acting as a competitive antagonist of the GABAA ρ1 receptors.
Assuntos
Cisteína/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Receptores de GABA-A/efeitos dos fármacos , Animais , Ligação Competitiva , Cloretos/metabolismo , Cistina/farmacologia , Relação Dose-Resposta a Droga , Etilmaleimida/farmacologia , Homocisteína/farmacologia , Humanos , Transporte de Íons/efeitos dos fármacos , Oócitos , Técnicas de Patch-Clamp , RNA Complementar/genética , Receptores de GABA-A/fisiologia , Proteínas Recombinantes/metabolismo , Xenopus laevis , Ácido gama-Aminobutírico/farmacologiaRESUMO
This study evaluated the anesthetic potential of thymol and carvacrol, and their influence on acetylcholinesterase (AChE) activity in the muscle and brain of silver catfish (Rhamdia quelen). The AChE activity of S-(+)-linalool was also evaluated. We subsequently assessed the effects of thymol and S-(+)-linalool on the GABAergic system. Fish were exposed to thymol and carvacrol (25, 50, 75, and 100 mg/L) to evaluate time for anesthesia and recovery. Both compounds induced sedation at 25 mg/L and anesthesia with 50-100 mg/L. However, fish exposed to carvacrol presented strong muscle contractions and mortality. AChE activity was increased in the brain of fish at 50 mg/L carvacrol and 100 mg/L thymol, and decreased in the muscle at 100 mg/L carvacrol. S-(+)-linalool did not alter AChE activity. Anesthesia with thymol was reversed by exposure to picrotoxin (GABAA antagonist), similar to the positive control propofol, but was not reversed by flumazenil (antagonist of benzodiazepine binding site), as observed for the positive control diazepam. Picrotoxin did not reverse the effect of S-(+)-linalool. Thymol exposure at 50 mg/L is more suitable than carvacrol for anesthesia in silver catfish, because this concentration did not cause any mortality or interference with AChE activity. Thymol interacted with GABAA receptors, but not with the GABAA/benzodiazepine site. In contrast, S-(+)-linalool did not act in GABAA receptors in silver catfish.
Assuntos
Acetilcolinesterase/metabolismo , Anestésicos/farmacologia , Peixes-Gato , Monoterpenos/farmacologia , Receptores de GABA-A/metabolismo , Timol/farmacologia , Acetilcolinesterase/fisiologia , Monoterpenos Acíclicos , Adjuvantes Anestésicos/farmacologia , Análise de Variância , Anestesia/veterinária , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Peixes-Gato/metabolismo , Cimenos , Diazepam/farmacologia , Antagonistas GABAérgicos/farmacologia , Músculos/efeitos dos fármacos , Músculos/enzimologia , Óleos Voláteis/química , Picrotoxina/farmacologia , Receptores de GABA-A/fisiologia , Reprodutibilidade dos Testes , Estatísticas não Paramétricas , Fatores de TempoRESUMO
The effects of cannabinoids in brain areas expressing cannabinoid receptors, such as hypothalamic nuclei, are not yet well known. Several studies have demonstrated the role of hypothalamic nuclei in the organisation of behavioural responses induced through innate fear and panic attacks. Panic-prone states are experimentally induced in laboratory animals through a reduction in the GABAergic activity. The aim of the present study was to examine panic-like elaborated defensive behaviour evoked by GABAA receptor blockade with bicuculline (BIC) in the dorsomedial division of the ventromedial hypothalamus (VMHdm). We also aimed to characterise the involvement of endocannabinoids and the CB1 cannabinoid receptor in the modulation of elaborated defence behavioural responses organised with the VMHdm. The guide-cannula was stereotaxicaly implanted in VMHdm and the animals were treated with anandamide (AEA) at different doses, and the effective dose was used after the pre-treatment with the CB1 receptor antagonist AM251, followed by GABAA receptor blockade in VMHdm. The results showed that the intra-hypothalamic administration of AEA at an intermediate dose (5 pmol) attenuated defence responses induced through the intra-VMHdm microinjection of bicuculline (40 ng). This effect, however, was inhibited when applied central microinjection of the CB1 receptor antagonist AM251 in the VMHdm. Moreover, AM251 potentiates de non-oriented escape induced by bicuculline, effect blocked by pre-treatment with the TRPV1 channel antagonist 6-I-CPS. These results indicate that AEA modulates the pro-aversive effects of intra-VMHdm-bicuculline treatment, recruiting CB1 cannabinoid receptors and the TRPV1 channel is involved in the AM251-related potentiation of bicuculline effects on non-oriented escape behaviour.
Assuntos
Reação de Fuga/fisiologia , Receptor CB1 de Canabinoide/fisiologia , Receptores de GABA-A/fisiologia , Canais de Cátion TRPV/fisiologia , Núcleo Hipotalâmico Ventromedial/fisiologia , Animais , Ácidos Araquidônicos/administração & dosagem , Bicuculina/administração & dosagem , Modelos Animais de Doenças , Endocanabinoides/administração & dosagem , Reação de Fuga/efeitos dos fármacos , Antagonistas de Receptores de GABA-A/administração & dosagem , Masculino , Transtorno de Pânico/induzido quimicamente , Transtorno de Pânico/fisiopatologia , Piperidinas/administração & dosagem , Alcamidas Poli-Insaturadas/administração & dosagem , Pirazóis/administração & dosagem , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacosRESUMO
This study evaluated the anesthetic potential of thymol and carvacrol, and their influence on acetylcholinesterase (AChE) activity in the muscle and brain of silver catfish (Rhamdia quelen). The AChE activity of S-(+)-linalool was also evaluated. We subsequently assessed the effects of thymol and S-(+)-linalool on the GABAergic system. Fish were exposed to thymol and carvacrol (25, 50, 75, and 100 mg/L) to evaluate time for anesthesia and recovery. Both compounds induced sedation at 25 mg/L and anesthesia with 50-100 mg/L. However, fish exposed to carvacrol presented strong muscle contractions and mortality. AChE activity was increased in the brain of fish at 50 mg/L carvacrol and 100 mg/L thymol, and decreased in the muscle at 100 mg/L carvacrol. S-(+)-linalool did not alter AChE activity. Anesthesia with thymol was reversed by exposure to picrotoxin (GABAA antagonist), similar to the positive control propofol, but was not reversed by flumazenil (antagonist of benzodiazepine binding site), as observed for the positive control diazepam. Picrotoxin did not reverse the effect of S-(+)-linalool. Thymol exposure at 50 mg/L is more suitable than carvacrol for anesthesia in silver catfish, because this concentration did not cause any mortality or interference with AChE activity. Thymol interacted with GABAA receptors, but not with the GABAA/benzodiazepine site. In contrast, S-(+)-linalool did not act in GABAA receptors in silver catfish.