RESUMO
Network dynamics are crucial for action and sensation. Changes in synaptic physiology lead to the reorganization of local microcircuits. Consequently, the functional state of the network impacts the output signal depending on the firing patterns of its units. Networks exhibit steady states in which neurons show various activities, producing many networks with diverse properties. Transitions between network states determine the output signal generated and its functional results. The temporal dynamics of excitation/inhibition allow a shift between states in an operational network. Therefore, a process capable of modulating the dynamics of excitation/inhibition may be functionally important. This process is known as disinhibition. In this review, we describe the effect of GABA levels and GABAB receptors on tonic inhibition, which causes changes (due to disinhibition) in network dynamics, leading to synchronous functional oscillations.
Assuntos
Fenômenos Fisiológicos do Sistema Nervoso , Receptores de GABA-B , Receptores de GABA-B/metabolismo , Neurônios/metabolismo , Inibição Neural/fisiologia , Ácido gama-Aminobutírico , Receptores de GABA-A , Antagonistas GABAérgicosRESUMO
INTRODUCTION: The kisspeptin gene Kiss1 is expressed in two hypothalamic areas: anteroventral periventricular nucleus/periventricular nucleus (AVPV/PeN) and arcuate nucleus (ARC), and also in gonads. Several pieces of evidence suggests that gamma-amino butyric acid B receptors (GABAB) signaling can regulate Kiss1 expression. Here, we inhibited GABAB signaling from PND2 to PND21 and evaluated the hypothalamic-pituitary-gonadal (HPG) axis. METHODS: BALB/c mice were treated on postnatal days 2-21 (PND2-PND21) with CGP55845 (GABAB antagonist) and evaluated in PND21 and adulthood: gene expression (qPCR) in the hypothalamus and gonads, hormones by radioimmunoassay, gonad histochemistry (H&E), puberty onset, and estrous cycles. RESULTS: At PND21, CGP inhibited Kiss1 and Tac2 and increased Pdyn and Gabbr1 in the ARC of both sexes and decreased Th only in female AVPV/PeN. Serum follicle-stimulating hormone (FSH) and testis weight were decreased in CGP-males, and puberty onset was delayed. In adults, Kiss1, Tac2, Pdyn, Pgr, Cyp19a1, and Gad1 were downregulated, while Gabbr1 was upregulated in the ARC of both sexes. In the AVPV/PeN, Kiss1, Th, Cyp19a1, and Pgr were decreased while Gad1 was increased in CGP-females, whereas Cyp19a1 was increased in CGP-males. Serum FSH was increased in CGP-males while prolactin was increased in CGP-females. Testosterone and progesterone were increased in ovaries from CGP-females, in which Kiss1, Cyp19a1, and Esr1 were downregulated while Hsd3b2 was upregulated, together with increased atretic and decreased ovulatory follicles. Testes from CGP-males showed decreased progesterone, increased Gabbr1, Kiss1, Kiss1r, and Esr2 and decreased Cyp19a1, and clear signs of seminiferous tubules atrophy. CONCLUSION: These results demonstrate that appropriate GABAB signaling during this critical prepubertal period is necessary for the normal development of the HPG axis.
Assuntos
Kisspeptinas , Progesterona , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Feminino , Hormônio Foliculoestimulante , Antagonistas GABAérgicos , Gônadas , Hipotálamo/metabolismo , Kisspeptinas/genética , Kisspeptinas/metabolismo , Masculino , Camundongos , Progesterona/metabolismo , Prolactina/metabolismo , Receptores de Kisspeptina-1/metabolismo , Maturidade Sexual/fisiologia , Testosterona/metabolismo , DesmameRESUMO
The endocannabinoid neurotransmission acting via local CB1 receptor in the bed nucleus of the stria terminalis (BNST) has been implicated in behavioral and physiological responses to emotional stress. However, the neural network related to this control is poorly understood. In this sense, the lateral hypothalamus (LH) is involved in stress responses, and BNST GABAergic neurons densely innervate this hypothalamic nucleus. However, a role of BNST projections to the LH in physiological responses to stress is unknown. Therefore, using male rats, we investigated the role of LH GABAergic neurotransmission in the regulation of cardiovascular responses to stress by CB1 receptors within the BNST. We observed that microinjection of the selective CB1 receptor antagonist AM251 into the BNST decreased the number of Fos-immunoreactive cells within the LH of rats submitted to acute restraint stress. Treatment of the BNST with AM251 also enhanced restraint-evoked tachycardia. Nevertheless, arterial pressure increase and sympathetically-mediated cutaneous vasoconstriction to restraint was not affected by CB1 receptor antagonism within the BNST. The effect of AM251 in the BNST on restraint-evoked tachycardia was abolished in animals pretreated with the selective GABAA receptor antagonist SR95531 in the LH. These results indicate that regulation of cardiovascular responses to stress by CB1 receptors in the BNST is mediated by GABAergic neurotransmission in the LH. Present data also provide evidence of the BNST endocannabinoid neurotransmission as a mechanism involved in LH neuronal activation during stressful events.
Assuntos
Endocanabinoides/fisiologia , Região Hipotalâmica Lateral/fisiologia , Angústia Psicológica , Núcleos Septais/fisiologia , Animais , Antagonistas de Receptores de Canabinoides/administração & dosagem , Antagonistas GABAérgicos/administração & dosagem , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Masculino , Modelos Neurológicos , Piperidinas/administração & dosagem , Pirazóis/administração & dosagem , Piridazinas/administração & dosagem , Ratos , Ratos Wistar , Núcleos Septais/efeitos dos fármacos , Estresse Psicológico/fisiopatologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Taquicardia/fisiopatologiaRESUMO
The expression of several hippocampal genes implicated in learning and memory processes requires that Ca2+ signals generated in dendritic spines, dendrites, or the soma in response to neuronal stimulation reach the nucleus. The diffusion of Ca2+ in the cytoplasm is highly restricted, so neurons must use other mechanisms to propagate Ca2+ signals to the nucleus. Here, we present evidence showing that Ca2+ release mediated by the ryanodine receptor (RyR) channel type-2 isoform (RyR2) contributes to the generation of nuclear Ca2+ signals induced by gabazine (GBZ) addition, glutamate uncaging in the dendrites, or high-frequency field stimulation of primary hippocampal neurons. Additionally, GBZ treatment significantly increased cyclic adenosine monophosphate response element binding protein (CREB) phosphorylation-a key event in synaptic plasticity and hippocampal memory-and enhanced the expression of Neuronal Per Arnt Sim domain protein 4 (Npas4) and RyR2, two central regulators of these processes. Suppression of RyR-mediated Ca2+ release with ryanodine significantly reduced the increase in CREB phosphorylation and the enhanced Npas4 and RyR2 expression induced by GBZ. We propose that RyR-mediated Ca2+ release induced by neuronal activity, through its contribution to the sequential generation of nuclear Ca2+ signals, CREB phosphorylation, Npas4, and RyR2 up-regulation, plays a central role in hippocampal synaptic plasticity and memory processes.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cálcio/metabolismo , Hipocampo/citologia , Neurônios/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Técnicas de Cultura de Células , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Antagonistas GABAérgicos/farmacologia , Ácido Glutâmico/farmacologia , Piridazinas/farmacologia , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Sinapses/fisiologia , Técnicas de Cultura de TecidosRESUMO
This study was conducted to evaluate the luteinizing hormone (LH) secretion pattern after gamma-aminobutyric acid (GABAA) antagonist to determine the effects of the GABAergic system on LH secretion during reproductive maturation in pre-pubertal Nellore heifers. Nellore heifers (nâ¯=â¯10) were administered a picrotoxin injection of 0.18â¯mg/kg, i.v. Blood samples were collected every 15â¯min for 3â¯h at different developmental stages (8, 10, 14 and 17 mo of age). Plasma concentrations of LH were quantified using an RIA (sensitivity of 0.04â¯ng/mL and CV of 15 %). There was an interaction between treatment and age (P = 0.034). Picrotoxin-treated heifers had lesser (Pâ¯≤⯠0.05) LH mean concentrations during a 3 h period at 10 and 17 mo of age compared to control heifers (Pâ¯≤⯠0.05). Comparing the period before and after Picrotoxin injection in the same animals, there was a 33 % decrease in LH concentration at 8 mo of age (P = 0.0165). These results indicate the GABAergic system has a stimulatory function in inducing LH secretion in pre-pubertal Nellore heifers. These findings corroborate previous results that GABA increases GnRH/LH secretion in other species during the pre-pubertal period.
Assuntos
Bovinos/fisiologia , Antagonistas GABAérgicos/farmacologia , Hormônio Luteinizante/sangue , Picrotoxina/farmacologia , Receptores de GABA/metabolismo , Maturidade Sexual/fisiologia , Animais , Bovinos/sangue , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Receptores de GABA/genéticaRESUMO
The proper pharmacological control of pain is a continuous challenge for patients and health care providers. Even the most widely used medications for pain treatment are still ineffective or unsafe for some patients, especially for those who suffer from chronic pain. Substances containing the chromone scaffold have shown a variety of biological activities, including analgesic effects. This work presents for the first time the centrally mediated antinociceptive activity of 5-O-methylcneorumchromone K (5-CK). Cold plate and tail flick tests in mice showed that the 5-CK-induced antinociception was dose-dependent, longer-lasting, and more efficacious than that induced by morphine. The 5-CK-induced antinociception was not reversed by the opioid antagonist naloxone. Topological descriptors (fingerprints) were employed to narrow the antagonist selection to further investigate 5-CK's mechanism of action. Next, based on the results of fingerprints analysis, functional antagonist assays were conducted on nociceptive tests. The effect of 5-CK was completely reversed in both cold plate and tail-flick tests by GABAA receptor antagonist bicuculline, but not by atropine or glibenclamide. Molecular docking studies suggest that 5-CK binds to the orthosteric binding site, with a similar binding profile to that observed for bicuculline and GABA. These results evidence that 5-CK has a centrally mediated antinociceptive effect, probably involving the activation of GABAergic pathways.
Assuntos
Analgésicos/farmacologia , Cromonas/farmacologia , Antagonistas GABAérgicos/farmacologia , Analgésicos/química , Animais , Sítios de Ligação , Cromonas/química , Antagonistas GABAérgicos/química , Camundongos , Simulação de Acoplamento Molecular , Nociceptividade , Ligação Proteica , Receptores de GABA/química , Receptores de GABA/metabolismoRESUMO
Epilepsy is a chronic neurobehavioral disorder whereby an imbalance between neurochemical excitation and inhibition at the synaptic level provokes seizures. Various experimental models have been used to study epilepsy, including that based on acute or chronic administration of Pentylenetetrazol (PTZ). In this study, a single PTZ dose (60 mg/kg) was administered to adult male rats and 30 min later, various neurobiological parameters were studied related to the transmission and modulation of excitatory impulses in pyramidal neurons of the hippocampal CA1 field. Rats experienced generalized seizures 1-3 min after PTZ administration, accompanied by elevated levels of Synaptophysin and Glutaminase. This response suggests presynaptic glutamate release is exacerbated to toxic levels, which eventually provokes neuronal death as witnessed by the higher levels of Caspase-3, TUNEL and GFAP. Similarly, the increase in PSD-95 suggests that viable dendritic spines are functional. Indeed, the increase in stubby and wide spines is likely related to de novo spinogenesis, and the regulation of neuronal excitability, which could represent a plastic response to the synaptic over-excitation. Furthermore, the increase in mushroom spines could be associated with the storage of cognitive information and the potentiation of thin spines until they are transformed into mushroom spines. However, the reduction in BDNF suggests that the activity of these spines would be down-regulated, may in part be responsible for the cognitive decline related to hippocampal function in patients with epilepsy.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Epilepsia/induzido quimicamente , Epilepsia/metabolismo , Antagonistas GABAérgicos/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Pentilenotetrazol/farmacologia , Células Piramidais/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Antagonistas GABAérgicos/administração & dosagem , Masculino , Pentilenotetrazol/administração & dosagem , Ratos , Ratos Sprague-DawleyRESUMO
Previous evidence indicated a potential mechanism that might support the fact that primates exhibit greater neural integration capacity as a result of the activation of different structures of the central nervous system, as compared to rodents. The current study aimed to provide further evidence to confirm previous findings by analyzing the patterns of c-Fos expression in more neocortical structures of rats and marmosets using a more robust quantitative technique and evaluating a larger number of brain areas. Nineteen Wistar rats and 21 marmosets (Callithrix jacchus) were distributed among control groups (animals without injections) and animals injected with pentylenetetrazol (PTZ) and euthanized at different time points after stimulus. Immunohistochemical detection of c-Fos was quantified using unbiased and efficient stereological cell counting in eight neocortical regions. Marmosets had a c-Fos expression that was notably more widely expressed (5× more cells) and longer lasting (up to 3 hr) than rats. c-Fos expression in rats presented similar patterns of expression according to the function of the brain cortical structures (associative, sensorial, and motor functions), which was not observed for marmosets (in which no clear pattern could be drawn, and a more diverse profile emerged). Our results provide evidence that the marmoset brain has a greater neuronal activation after intense stimulation by means of PTZ and a more complex pattern of brain activation. We speculate that these functional differences may contribute for the understanding of the different neuronal processing capacities of the neocortex in these mammals' orders.
Assuntos
Neocórtex/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Callithrix , Antagonistas GABAérgicos/farmacologia , Masculino , Neocórtex/efeitos dos fármacos , Pentilenotetrazol/farmacologia , Ratos , Ratos WistarRESUMO
Considering the involvement of GABAergic system in the action of the fast-acting antidepressant ketamine, and that agmatine may exert an antidepressant-like effect through mechanisms similar to ketamine, the purpose of the present study was to evaluate the involvement of GABAA and GABAB receptors in the antidepressant-like effect of agmatine. The administration of muscimol (0.1 mg/kg, i.p., GABAA receptor agonist) or diazepam (0.05 mg/kg, p.o., GABAA receptor positive allosteric modulator) at doses that caused no effect in the tail suspension test (TST) combined with a subeffective dose of agmatine (0.0001 mg/kg, p.o.) produced a synergistic antidepressant-like effect in the TST. In another set of experiments, the administration of baclofen (1 mg/kg, i.p., GABAB receptor agonist) abolished the reduction of immobility time in the TST elicited by agmatine (0.1 mg/kg, p.o., active dose). In another cohort of animals, treatment with NMDA (0.1 pmol/site, i.c.v.) prevented the antidepressant-like effect of the combined administration of agmatine and muscimol as well as ketamine and muscimol in the TST. Results suggest that the effect of agmatine in the TST may involve an activation of GABAA receptors dependent on NMDA receptor inhibition, similar to ketamine, as well as modulation of GABAB receptors.
Assuntos
Agmatina/uso terapêutico , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Neurônios GABAérgicos/efeitos dos fármacos , Receptores de GABA/fisiologia , Agmatina/farmacologia , Animais , Antidepressivos/farmacologia , Depressão/psicologia , Feminino , Agonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/farmacologia , Neurônios GABAérgicos/fisiologia , Elevação dos Membros Posteriores/efeitos adversos , Elevação dos Membros Posteriores/psicologia , Camundongos , Ácido gama-Aminobutírico/fisiologiaRESUMO
Few behavioral tests allow measuring several characteristics and most require training, complex analyses, and/or are time-consuming. We present an apparatus based on rat exploratory behavior. Composed of three different environments, it allows the assessment of more than one behavioral characteristic in a short 3-min session. Factorial analyses have defined three behavioral dimensions, which we named Exploration, Impulsivity, and Self-protection. Behaviors composing the Exploration factor were increased by chlordiazepoxide and apomorphine and decreased by pentylenetetrazole. Behaviors composing the Impulsivity factor were increased by chlordiazepoxide, apomorphine, and both acute and chronic imipramine treatments. Behaviors composing the Self-protection factor were decreased by apomorphine. We submitted Wistar rats to the open-field test, the elevated-plus maze, and to the apparatus we are proposing. Measures related to exploratory behavior in all three tests were correlated. Measures composing the factors Impulsivity and Self-protection did not correlate with any measures from the two standard tests. Also, compared with existing impulsivity tests, the one we proposed did not require previous learning, training, or sophisticated analysis. Exploration measures from our test are as easy to obtain as the ones from other standard tests. Thus, we have proposed an apparatus that measured three different behavioral characteristics, was simple and fast, did not require subjects to be submitted to previous learning or training, was sensitive to drug treatments, and did not require sophisticated data analyses.
Assuntos
Ansiedade/psicologia , Comportamento Animal/fisiologia , Pesquisa Comportamental/instrumentação , Comportamento Exploratório/fisiologia , Medo/fisiologia , Comportamento Impulsivo/fisiologia , Animais , Ansiolíticos/farmacologia , Antidepressivos Tricíclicos/farmacologia , Apomorfina/farmacologia , Comportamento Animal/efeitos dos fármacos , Clordiazepóxido/farmacologia , Agonistas de Dopamina/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Medo/efeitos dos fármacos , Antagonistas GABAérgicos/farmacologia , Comportamento Impulsivo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Modelos Animais , Pentilenotetrazol/farmacologia , Ratos Wistar , Fatores de TempoRESUMO
The lateral hypothalamus (LH) has been described as one of the hypothalamic areas involved in the behavioral and physiological responses triggered by aversive stimuli. Previous studies indicated involvement of the LH in cardiovascular responses to stress. Despite this evidence, the local neurochemical mechanisms involved in LH control of stress responses is still poorly understood. Therefore, in the present study, we investigated the role of GABAergic neurotransmission within the LH in cardiovascular responses induced by an acute session of restraint stress in rats. For this, we evaluated the effect of bilateral microinjection of selective antagonists of either GABAA or GABAB receptors into the LH on arterial pressure increase, heart rate (HR) increase and reduction in tail skin temperature induced by restraint stress. We found that microinjection of the selective GABAA receptor antagonist SR95531 into the LH decreased the increase in HR caused by restraint stress, but without affecting the increase in arterial pressure increase or the reduction in tail skin temperature. Conversely, LH treatment with the selective GABAB receptor antagonist CGP35348 did not affect the restraint-evoked cardiovascular changes. These findings indicate that GABAergic neurotransmission in the LH, acting through activation of local GABAA receptors, plays a facilitatory role in the tachycardic response observed during aversive threats.
Assuntos
Região Hipotalâmica Lateral/metabolismo , Angústia Psicológica , Receptores de GABA-A/metabolismo , Receptores de GABA-B/metabolismo , Estresse Psicológico/metabolismo , Taquicardia/metabolismo , Animais , Antagonistas GABAérgicos/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Masculino , Microinjeções , Ratos , Ratos Wistar , Estresse Psicológico/psicologia , Taquicardia/psicologiaRESUMO
Epilepsy is characterized by abnormal and recurrent hyperexcitability in brain cells. Various comorbidities are associated with epilepsy, including irritability and aggressive behavior. Aggression is a negative effect observed in epileptic patients that may be harmful to other individuals, impairing social relations. Thus, developing novel experimental models to assess behavioral phenotypes that may comorbid with neurological disorders are of great interest. Here, we investigate whether pentylenetetrazole (PTZ) increases aggression in zebrafish following a single exposure. Animals were exposed to 10 mM PTZ for 20 min and aggression-towards mirror was measured at different time intervals after recovering period (1 h, 3 h, 6 h, 24 h, 48 h, and 72 h). We observed that zebrafish showed exacerbated aggression, as well as an increased number of entries in the virtual conspecific area from 1 h to 48 h after PTZ. However, no behavioral differences were observed after 72 h. Overall, our novel findings show that a single PTZ exposure evokes aggression in a time-dependent manner, reinforcing the use of zebrafish models to explore epilepsy-related comorbidities.
Assuntos
Agressão/efeitos dos fármacos , Antagonistas GABAérgicos/administração & dosagem , Pentilenotetrazol/administração & dosagem , Convulsões/induzido quimicamente , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Masculino , Peixe-ZebraRESUMO
Few behavioral tests allow measuring several characteristics and most require training, complex analyses, and/or are time-consuming. We present an apparatus based on rat exploratory behavior. Composed of three different environments, it allows the assessment of more than one behavioral characteristic in a short 3-min session. Factorial analyses have defined three behavioral dimensions, which we named Exploration, Impulsivity, and Self-protection. Behaviors composing the Exploration factor were increased by chlordiazepoxide and apomorphine and decreased by pentylenetetrazole. Behaviors composing the Impulsivity factor were increased by chlordiazepoxide, apomorphine, and both acute and chronic imipramine treatments. Behaviors composing the Self-protection factor were decreased by apomorphine. We submitted Wistar rats to the open-field test, the elevated-plus maze, and to the apparatus we are proposing. Measures related to exploratory behavior in all three tests were correlated. Measures composing the factors Impulsivity and Self-protection did not correlate with any measures from the two standard tests. Also, compared with existing impulsivity tests, the one we proposed did not require previous learning, training, or sophisticated analysis. Exploration measures from our test are as easy to obtain as the ones from other standard tests. Thus, we have proposed an apparatus that measured three different behavioral characteristics, was simple and fast, did not require subjects to be submitted to previous learning or training, was sensitive to drug treatments, and did not require sophisticated data analyses.
Assuntos
Animais , Masculino , Ansiedade/psicologia , Comportamento Animal/fisiologia , Pesquisa Comportamental/instrumentação , Comportamento Exploratório/fisiologia , Medo/fisiologia , Comportamento Impulsivo/fisiologia , Fatores de Tempo , Ansiolíticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Apomorfina/farmacologia , Clordiazepóxido/farmacologia , Ratos Wistar , Aprendizagem em Labirinto/efeitos dos fármacos , Antagonistas GABAérgicos/farmacologia , Agonistas de Dopamina/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Medo/efeitos dos fármacos , Comportamento Impulsivo/efeitos dos fármacos , Antidepressivos Tricíclicos/farmacologiaRESUMO
Background: Diverse forms of long-term potentiation (LTP) have been described, but one of the most investigated is encountered in the glutamatergic synapses of the hippocampal cornu Ammonis (CA1) subfield. However, little is known about synaptic plasticity in wildlife populations. Laboratory animals are extremely inbred populations that have been disconnected from their natural environment and so their essential ecological aspects are entirely absent. Proechimys are small rodents from Brazil's Amazon rainforest and their nervous systems have evolved to carry out specific tasks of their unique ecological environment. It has also been shown that long-term memory duration did not persist for 24-h in Proechimys, in contrast to Wistar rats, when both animal species were assessed by the plus-maze discrimination avoidance task and object recognition test. Methods: In this work, different protocols, such as theta burst, single tetanic burst or multiple trains of high frequency stimulation (HFS), were used to induce LTP in hippocampal brain slices of Proechimys and Wistar rats. Results: A protocol-independent fast decay of early-phase LTP at glutamatergic synapses of the CA1 subfield was encountered in Proechimys. Long-term depression (LTD) and baseline paired-pulse facilitation (PPF) were investigated but no differences were found between animal species. Input/output (I/O) relationships suggested lower excitability in Proechimys in comparison to Wistar rats. Bath application of d-(-)-2-amino-5-phosphonopentanoicacid (D-AP5) and CNQX prevented the induction of LTP in both Proechimys and Wistar. However, in marked contrast to Wistar rats, LTP induction was not facilitated by the GABAA antagonist in the Amazon rodents, even higher concentrations failed to facilitate LTP in Proechimys. Next, the effects of GABAA inhibition on spontaneous activity as well as evoked field potentials (FPs) were evaluated in CA1 pyramidal cells. Likewise, much lower activity was detected in Proechimys brain slices in comparison to those of the Wistar rats. Conclusions: These findings suggest a possible high inhibitory tone in the CA1 network mediated by GABAA receptors in the Amazon rodents. Currently, neuroscience research still seeks to reveal molecular pathways that control learning and memory processes, Proechimys may prove useful in identifying such mechanisms in complement to traditional animal models.
Assuntos
Região CA1 Hipocampal/fisiologia , Potenciação de Longa Duração/fisiologia , Rede Nervosa/fisiologia , Inibição Neural/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Diazepam/farmacologia , Antagonistas GABAérgicos/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Rede Nervosa/efeitos dos fármacos , Inibição Neural/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Picrotoxina/farmacologia , Ratos , Ratos Wistar , Especificidade da EspécieRESUMO
The dorsal hippocampus (DH) is involved in the modulation of the cardiac baroreflex function. There is a wide expression of the NMDA and AMPA/Kainate receptors within the DH. Glutamate administration into the DH triggers both tachycardia and pressor responses. Moreover, GABAergic interneurons and endocannabinoid system play an important role in modulation of the activity of glutamatergic neurons within the DH. Therefore, the present work aimed to evaluate the involvement of the glutamatergic, GABAergic, and endocannabinoid neurotransmissions within the DH in cardiac baroreflex function in rats. We have used the technique of vasoactive drugs infusion to build both sigmoidal curves and linear regressions to analyze the cardiac baroreflex function. Bilateral injection into the DH of DL-AP7, a NMDA receptor antagonist (10 or 50 nmol/500 nL), or NBQX, an AMPA/Kainate antagonist (100 nmol/ 500 nL), reduced the cardiac baroreflex function. On the other hand, bilateral injection of Bicuculline, a GABAA receptor antagonist (1 nmol/500 nL), or AM251, a CB1 receptor antagonist (10 or 100 pmol/500 nL), increased the cardiac baroreflex function. Furthermore, 1 nmol/500 nL of the NMDA receptor antagonist, when administrated alone, was ineffective to change baroreflex function, but it was able to inhibit the alteration in the cardiac baroreflex function elicited by the dose of 100 pmol/500 nL of the CB1 receptor antagonist. Taken together, these findings suggest that glutamatergic, GABAergic, and endocannabinoid neurotransmissions interact each other within the DH to modulate the cardiac baroreflex function.
Assuntos
Barorreflexo , Coração/fisiologia , Hipocampo/metabolismo , Receptores de Canabinoides/metabolismo , Receptores de GABA/metabolismo , Receptores de Glutamato/metabolismo , Animais , Antagonistas de Receptores de Canabinoides/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas GABAérgicos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Ratos , Ratos Wistar , Transmissão SinápticaRESUMO
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
OBJECTIVES: Glutaric acidemia type I (GA-I) is an inherited neurometabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase (GCDH) and characterized by increased levels of glutaric, 3-OH-glutaric, and glutaconic acids in the brain parenchyma. The increment of these organic acids inhibits glutamate decarboxylase (GAD) and consequently lowers the γ-aminobutyric acid (GABA) synthesis. Untreated patients exhibit severe neurologic deficits during development, including epilepsy, especially following an acute encephalopathy outbreak. In this work, we evaluated the role of the GABAergic system on epileptogenesis in GA-I using the Gcdh-/- mice exposed to a high lysine diet (Gcdh-/- -Lys). METHODS: Spontaneous recurrent seizures (SRS), seizure susceptibility, and changes in brain oscillations were evaluated by video-electroencephalography (EEG). Cortical GABAergic synaptic transmission was evaluated using electrophysiologic and neurochemical approaches. RESULTS: SRS were observed in 72% of Gcdh-/- -Lys mice, whereas no seizures were detected in age-matched controls (Gcdh+/+ or Gcdh-/- receiving normal diet). The severity and number of PTZ-induced seizures were higher in Gcdh-/- -Lys mice. EEG spectral analysis showed a significant decrease in theta and gamma oscillations and predominant delta waves in Gcdh-/- -Lys mice, associated with increased EEG left index. Analysis of cortical synaptosomes revealed a significantly increased percentage of glutamate release and decreased GABA release in Gcdh-/- -Lys mice that were associated with a decrease in cortical GAD immunocontent and activity and confirmed by reduced frequency of inhibitory events in cortical pyramidal cells. SIGNIFICANCE: Using an experimental model with a phenotype similar to that of GA-I in humans-the Gcdh-/- mice under high lysine diet (Gcdh-/- -Lys)-we provide evidence that a reduction in cortical inhibition of Gcdh-/- -Lys mice, probably induced by GAD dysfunction, leads to hyperexcitability and increased slow oscillations associated with neurologic abnormalities in GA-I. Our findings offer a new perspective on the pathophysiology of brain damage in GA-I.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Encefalopatias Metabólicas/genética , Encéfalo/efeitos dos fármacos , Epilepsia/genética , Glutaril-CoA Desidrogenase/deficiência , Glutaril-CoA Desidrogenase/genética , Ácido gama-Aminobutírico/efeitos dos fármacos , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Animais , Western Blotting , Encefalopatias Metabólicas/metabolismo , Cromatografia Líquida de Alta Pressão , Epilepsia/metabolismo , Antagonistas GABAérgicos/farmacologia , Glutamato Descarboxilase , Ácido Glutâmico/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Glutaril-CoA Desidrogenase/metabolismo , Camundongos , Camundongos Knockout , Pentilenotetrazol/farmacologia , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
Inhibitory GABAergic and glycinergic neurotransmission in the spinal cord play a central role in the regulation of neuronal excitability, by maintaining a balance with the glutamate-mediated excitatory transmission. Glutamatergic agonists infusion in the spinal cord induce motor neuron death by excitotoxicity, leading to motor deficits and paralysis, but little is known on the effect of the blockade of inhibitory transmission. In this work we studied the effects of GABAergic and glycinergic blockade, by means of microdialysis perfusion (acute administration) and osmotic minipumps infusion (chronic administration) of GABA and glycine receptors antagonists directly in the lumbar spinal cord. We show that acute glycinergic blockade with strychnine or GABAergic blockade with bicuculline had no significant effects on motor activity and on motor neuron survival. However, chronic bicuculline infusion, but not strychnine, induced ipsilateral gait alterations, phalange flaccidity and significant motor neuron loss, and these effects were prevented by AMPA receptor blockade with CNQX but not by NMDA receptor blockade with MK801. In addition, we demonstrate that the chronic infusion of bicuculline enhanced the excitotoxic effect of AMPA, causing faster bilateral paralysis and increasing motor neuron loss. These findings indicate a relevant role of GABAergic inhibitory circuits in the regulation of motor neuron excitability and suggest that their alterations may be involved in the neurodegeneration processes characteristic of motor neuron diseases such as amyotrophic lateral sclerosis.
Assuntos
Bicuculina/toxicidade , Antagonistas GABAérgicos/toxicidade , Atividade Motora/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Degeneração Neural/induzido quimicamente , Medula Espinal/efeitos dos fármacos , Estricnina/toxicidade , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Animais , Atrofia/induzido quimicamente , Bicuculina/antagonistas & inibidores , Maleato de Dizocilpina/farmacologia , Interações Medicamentosas , Marcha/efeitos dos fármacos , Masculino , Hipotonia Muscular/induzido quimicamente , Ratos , Receptores de Glicina/antagonistas & inibidores , Estricnina/antagonistas & inibidores , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/toxicidadeRESUMO
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
Animais , Acetilcolinesterase/metabolismo , Anestésicos/farmacologia , Peixes-Gato , Monoterpenos/farmacologia , Receptores de GABA-A/metabolismo , Timol/farmacologia , Acetilcolinesterase/fisiologia , Adjuvantes Anestésicos/farmacologia , Análise de Variância , Anestesia/veterinária , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Peixes-Gato/metabolismo , 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 cannabinoid receptor type 1 (CB1) is highly expressed in the dorsal portion of hippocampus - a brain region that has been involved in the control of conditioned emotional response (CER) in the contextual fear conditioning (CFC) model. These responses are characterized by increased freezing behavior and autonomic parameters. Moreover, CB1 receptors activation negatively modulate the release of several neurotransmitters, including glutamate and GABA, which also have been related to modulation of CER. Therefore, our aim was to investigate the involvement of CB1 receptors in the dorsal hippocampus on CER expression. Independent groups of male Wistar rats submitted to the contextual fear conditioning received bilateral intra-hippocampal injections (500 nL/side) of the following drugs or vehicle before re-exposure to the aversive context: AM251 (CB1 antagonist; 0.1, 0.3 and 1nmol); AP7 (NMDA antagonist; 1nmol)+AM251 (0.3nmol); NPLA (0.01nmol; nNOS inhibitor)+AM251 (0.3nmol); Bicuculline (1.3pmol; GABAA antagonist)+AM251 (0.1 and 1nmol). In the present paper, AM251 (0.3nmol) increased CER, while this response was prevented by both AP7 and NPLA pretreatment. After pretreatment with Bicuculline, the lower and higher ineffective doses of AM251 were able to increase the CER, supporting the balance between GABAergic and glutamatergic mechanisms controlling this response. Our results suggest that increased CER evoked by CB1 blockade in the dorsal hippocampus depends on NMDA receptor activation and NO formation. Moreover, a fine-tune control promoted by GABAergic and glutamatergic mechanisms in this brain area modulate the CER after CB1 blockade.