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1.
J Neurochem ; 156(6): 897-916, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32750173

RESUMO

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 Sexuais
2.
Naunyn Schmiedebergs Arch Pharmacol ; 393(10): 1931-1939, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32447465

RESUMO

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/fisiologia
3.
Rev. bras. pesqui. méd. biol ; Braz. j. med. biol. res;53(8): e10034, 2020. graf
Artigo em Inglês | LILACS, Coleciona SUS | ID: biblio-1132538

RESUMO

Contradictory findings suggest that the behavioral and abuse-related effects of ethanol are mediated by its action at α1 subunit-containing GABAA (α1GABAA) receptors. In the present study, we investigated the effects of a sub-chronic post-ethanol administration treatment with zolpidem, an α1-preferring positive allosteric modulator at GABAA receptors, on the subsequent expression of ethanol-induced behavioral sensitization in mice. Animals received ethanol (1.8 g/kg, ip) or saline treatments every other day for 15 days (8 treatment sessions) and were subsequently treated with zolpidem (0.5 mg/kg, ip) or vehicle 4 times on alternate days. At the end of the treatment phase, animals were challenged with saline or ethanol on separate days for the evaluation of the expression of conditioned locomotion and behavioral sensitization. Eight-day treatment with ethanol did not lead to the development of ethanol-induced behavioral sensitization. Animals treated with ethanol and subsequently administered vehicle showed similar locomotion frequencies during the last ethanol challenge compared to the control group receiving ethanol for the first time. Animals treated with ethanol and subsequently administered zolpidem expressed behavioral sensitization to ethanol during the ethanol challenge. The present study adds to the literature by providing further evidence of a role of α1GABAA receptors on the behavioral effects of ethanol. Because of the current highly prevalent co-abuse of ethanol and benzodiazepine drugs in humans, the use of zolpidem and other α1GABAA receptor ligands during ethanol withdrawal should be monitored carefully.


Assuntos
Animais , Masculino , Coelhos , Agonistas GABAérgicos/farmacologia , Etanol , Zolpidem/farmacologia , Benzodiazepinas , Receptores de GABA-A , Locomoção
4.
Neurotoxicology ; 74: 272-281, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31415799

RESUMO

The signal transmission in the nervous system operates through a sensitive balance between excitatory (E) inputs and inhibitory (I) responses. Imbalances in this system contribute to the development of pathologies such as seizures. In Caenorhabditis elegans, the locomotor circuit operates via the coordinated activity of cholinergic excitatory (E) and GABAergic inhibitory (I) transmission. Changes in E/I inputs can cause uncontrolled electrical discharges, mimicking the physiology of seizures. Molecules derived from 1,3,4-oxadiazole have been found to exhibit diverse biological activities, including anticonvulsant effect. In this work, we study the activity of the compound 2-[(4-methoxyphenylselenyl)methylthio]-5-phenyl-1,3,4-oxadiazole (MPMT-OX) in the GABAergic and cholinergic systems. We demonstrate that MPMT-OX reduced the locomotor activity of C. elegans with a normal balance between the E/I systems and increased the resistance to paralysis in worms exposed to pentylenetetrazol and aldicarb. MPMT-OX increased seizure resistance and assisted in the recovery of locomotor activity in worms with deletions in the genes unc-46, which regulates the transport of GABA into vesicles, and unc-49, which encodes the GABAA receptor. C. elegans with deletions in the unc-25 and unc-47 genes did not respond to treatment. Therefore, we suggest that the compound MPMT-OX upregulates GABAergic signaling in a manner dependent on the unc-25 gene, which is responsible for GABA synthesis, and unc-47, which encodes the vesicular GABA transporter.


Assuntos
Comportamento Animal/efeitos dos fármacos , Caenorhabditis elegans , Agonistas GABAérgicos/farmacologia , Oxidiazóis/farmacologia , Convulsões/prevenção & controle , Transmissão Sináptica/efeitos dos fármacos , Animais , Proteínas de Caenorhabditis elegans/biossíntese , Proteínas de Caenorhabditis elegans/genética , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Sistema Nervoso Parassimpático/efeitos dos fármacos , Convulsões/induzido quimicamente , Convulsões/psicologia , Vesículas Sinápticas/efeitos dos fármacos , Ácido gama-Aminobutírico/fisiologia
5.
Exp Neurol ; 302: 46-56, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29305892

RESUMO

Parkinson's disease (PD) is characterized by a reduction in the number of dopaminergic neurons of the substantia nigra (SNpc), accompanied by motor and non-motor deficiencies such as respiratory failure. Here, our aim was to investigate possible neuronal communications between the SNpc and chemoreceptor neurons within the retrotrapezoid nucleus (RTN), in order to explain neurodegeneration and the loss of breathing function in the 6-OHDA PD animal model. Male Wistar rats received tracer injections in the SNpc, RTN and periaqueductal gray (PAG) regions to investigate the projections between those regions. The results showed that neurons of the SNpc project to the RTN by an indirect pathway that goes through the PAG region. In different groups of rats, reductions in the density of neuronal markers (NeuN) and the number of catecholaminergic varicosities in PAG, as well as reductions in the number of CO2-activated PAG neurons with RTN projections, were observed in a 6-OHDA model of PD. Physiological experiments showed that inhibition of the PAG by bilateral injection of muscimol did not produce resting breathing disturbances but instead reduced genioglossus (GGEMG) and abdominal (AbdEMG) muscle activity amplitude induced by hypercapnia in control rats that were urethane-anesthetized, vagotomized, and artificially ventilated. However, in a model of PD, we found reductions in resting diaphragm muscle activity (DiaEMG) and GGEMG frequencies, as well as in hypercapnia-induced DiaEMG, GGEMG and AbdEMG frequencies and GGEMG and AbdEMG amplitudes. Therefore, we can conclude that there is an indirect pathway between neurons of the SNpc and RTN that goes through the PAG and that there is a defect of this pathway in an animal model of PD.


Assuntos
Substância Cinzenta/patologia , Vias Neurais/patologia , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Substância Cinzenta Periaquedutal/patologia , Ventilação Pulmonar/fisiologia , Substância Negra/patologia , Animais , Células Quimiorreceptoras/fisiologia , Modelos Animais de Doenças , Agonistas GABAérgicos/farmacologia , Glutamato Descarboxilase/metabolismo , Substância Cinzenta/metabolismo , Hipercapnia/etiologia , Masculino , Muscimol/farmacologia , Oxidopamina/toxicidade , Doença de Parkinson/etiologia , Fosfopiruvato Hidratase/metabolismo , Ventilação Pulmonar/efeitos dos fármacos , Ratos , Ratos Wistar , Simpatolíticos/toxicidade , Tirosina 3-Mono-Oxigenase/metabolismo
6.
Brain Res Bull ; 106: 21-9, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24831566

RESUMO

The dorsal raphe nucleus (DRN) is involved in the control of several physiological functions, including nociceptive modulation. This nucleus is one of the main sources of serotonin to the CNS and neuromodulators such as opioids and GABA may be are important for its release. This study evaluated the influence of serotonergic, GABAergic and opioidergic stimulation, as well as their interactions in the DRN, on vocalization nociceptive response during a peripheral noxious stimulus application in guinea pigs. Morphine (1.1 nmol), bicuculline (0.50 nmol) and alpha-methyl-5-HT (1.6 nmol) microinjection on the DRN produces antinociception. The antinociception produced by morphine (1.1 nmol) and alpha-methyl-5-HT (1.6 nmol) into the DRN was blocked by prior microinjection of naloxone (0.7 nmol). The alpha-methyl-5-HT effect blocked by naloxone may indicate the existence of 5-HT2A receptors on enkephalinergic interneurons within the dorsal raphe. Pretreatment with muscimol (0.26 nmol) also prevented the antinociceptive effect caused by morphine (1.1 nmol) when administered alone at the same site, indicating an interaction between GABAergic and opioidergic interneurons. The antinociception produced by bicuculline (0.5 nmol) in the DRN was blocked by prior administration of 8-OH-DPAT (0.5 nmol), a 5-HT1A agonist. This may indicate that the 5-HT autoreceptor activation by 8-OH-DPAT at DRN effector neurons can oppose the bicuculline disinhibition effect applied to the same effectors. Thus, we suggest that 5-HT2 receptor activation in the DRN promotes endorphin/enkephalin release that may disinhibit efferent serotonergic neurons of this present structure by inhibiting GABAergic interneurons, resulting in antinociception.


Assuntos
Analgésicos Opioides/farmacologia , Núcleo Dorsal da Rafe/fisiologia , Nociceptividade/fisiologia , Serotonina/fisiologia , Vocalização Animal/fisiologia , Ácido gama-Aminobutírico/fisiologia , Animais , Bicuculina/farmacologia , Núcleo Dorsal da Rafe/efeitos dos fármacos , Agonistas GABAérgicos/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Cobaias , Masculino , Morfina/farmacologia , Muscimol/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Nociceptividade/efeitos dos fármacos , Serotonina/análogos & derivados , Transmissão Sináptica , Vocalização Animal/efeitos dos fármacos
7.
Neurosci Lett ; 558: 91-6, 2014 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-24269979

RESUMO

Studies have demonstrated that median preoptic nucleus (MnPO) neurons play a role in organizing the cardiovascular responses induced by changes in the circulating blood volume. The present study examined whether the MnPO controls cardiovascular function. Male Wistar normotensive (NT) rats and spontaneously hypertensive rats (SHRs; 250-300 g) were anesthetized with urethane (1.2 g kg(-1), i.v.) and instrumented for recordings of mean arterial blood pressure (MAP) and renal blood flow (RBF). The renal vascular conductance (RVC) was calculated as the RBF:MAP ratio and was expressed as a percentage of the baseline value. In the NT rats (n=6), MnPO inhibition produced a MAP reduction (-8.1±1.1 mmHg, p<0.05). In the SHRs (n=6), the MAP response to MnPO inhibition was significantly greater (-22.3±4 mmHg, p<0.05) than in the NT rats. Furthermore, the increase in the RVC was higher in the SHRs (10.9±3.3%, p<0.05). Histological analyses confirmed that the injection sites were confined to the MnPO. We conclude that the MnPO is involved in the tonic regulation of blood pressure in NT rats. Moreover, the greater cardiovascular response to MnPO inhibition observed in the SHRs strongly suggests that the MnPO may contribute to the pathophysiology of essential hypertension.


Assuntos
Pressão Sanguínea/fisiologia , Área Pré-Óptica/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Agonistas GABAérgicos/administração & dosagem , Agonistas GABAérgicos/farmacologia , Injeções Intraventriculares , Rim/irrigação sanguínea , Masculino , Microinjeções , Muscimol/administração & dosagem , Muscimol/farmacologia , Área Pré-Óptica/efeitos dos fármacos , Ratos Endogâmicos SHR , Ratos Wistar , Fluxo Sanguíneo Regional , Especificidade da Espécie , Resistência Vascular
8.
Pharmacol Rep ; 65(3): 566-78, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23950579

RESUMO

BACKGROUND: The effect of the agonism on γ-aminobutyric acid (GABA) receptors was studied within medial prefrontal cortex (mPFC), amygdala (AMY) and ventral hipocampus (VH) in the plus-maze test in male rats bilaterally cannulated. These structures send glutamatergic projections to the nucleus accumbens septi (NAS), in which interaction and integration between these afferent pathways has been described. In a previous study of our group, blockade of glutamatergic transmission within NAS induced an anxiolytic like effect. METHODS: Three rat groups received either saline or dipotassium chlorazepate (1 or 2 µg/1 µl solution) 15 min before testing. Time spent in the open arms (TSOA), time per entry (TPE), extreme arrivals (EA), open and closed arms entries (OAE, CAE) and relationship between open- and closed-arms quotient (OCAQ) were recorded. RESULTS: In the AMY injected group TSOA, OAE and EA were increased by the higher doses of dipotassium chlorazepate (p < 0.01). In the mPFC, TPE was decreased by both doses (p < 0.05). Injection within ventral hippocampus (VH) decreased TSOA, OAE and OCAQ with lower doses (p < 0.05). When the three studied saline groups were compared, TSOA, OAE, EA and OCAQ were enhanced in the VH group when compared to mPFC and AMY (p < 0.001). Insertion of inner canula (p < 0.001, p < 0.01, p < 0.01) and saline injection showed an increasing significant difference (p < 0.001 in all cases) with the action of guide cannula alone within VH in TSOA, OAE and EA. CONCLUSION: We conclude that the injection of dipotassium chlorazepate has a differential effect depending of the brain area, leading to facilitatory and inhibitory effects on anxiety processing.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Clorazepato Dipotássico/administração & dosagem , Fármacos Atuantes sobre Aminoácidos Excitatórios/administração & dosagem , Hipocampo/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Animais , Ansiolíticos/administração & dosagem , Ansiedade/tratamento farmacológico , Agonistas GABAérgicos/administração & dosagem , Masculino , Ratos
9.
Physiol Behav ; 118: 80-7, 2013 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-23685230

RESUMO

The inferior colliculus (IC) is primarily involved in the processing of acoustic stimuli, including those emitted by prey and predators. The role of the central nucleus of the IC (CIC) in fear and anxiety has been suggested based on electrophysiological, behavioral and immunohistochemical studies. The reactivity of high-anxiety rats (HA) to diverse challenges is different from low-anxiety ones (LA). In humans and laboratory animals, pathological anxiety is often accompanied by heightened vigilance and alertness, hyperactivity of the amygdala (AM), and increased amplitude of the auditory evoked potentials (AEP) from the IC. This study aims to evaluate the influence of the inactivation of the central (CEA) and basolateral (BLA) nuclei of the amygdala, after local infusions of the full GABAA agonist muscimol (1nmol/0.2µl), on the AEP elicited in the CIC of rats tested under a learned fear state. Our results showed that both BLA and CEA inactivation change the expression of conditioned fear, in a paradigm using the context as the conditioned stimulus (CS). These changes are correlated to the innate anxiety levels of the animals. It is supposed that this shortcoming is in addition to the imbalance between the regulatory role of the top-down and bottom-up processes in the control of anxiety.


Assuntos
Tonsila do Cerebelo/fisiologia , Ansiedade/fisiopatologia , Ansiedade/psicologia , Medo/fisiologia , Audição/fisiologia , Animais , Condicionamento Psicológico/fisiologia , Potenciais Evocados Auditivos/fisiologia , Agonistas GABAérgicos/farmacologia , Colículos Inferiores/metabolismo , Aprendizagem/fisiologia , Masculino , Microinjeções , Muscimol/farmacologia , Ratos , Ratos Wistar , Ácido gama-Aminobutírico/metabolismo
10.
Behav Brain Funct ; 9: 17, 2013 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-23642235

RESUMO

BACKGROUND: Activation of GABA(B) receptors with baclofen into the lateral parabrachial nucleus (LPBN) induces ingestion of water and 0.3 M NaCl in fluid replete rats. However, up to now, no study has investigated the effects of baclofen injected alone or combined with GABA(B) receptor antagonist into the LPBN on water and 0.3 M NaCl intake in rats with increased plasma osmolarity (rats treated with an intragastric load of 2 M NaCl). Male Wistar rats with stainless steel cannulas implanted bilaterally into the LPBN were used. RESULTS: In fluid replete rats, baclofen (0.5 nmol/0.2 µl), bilaterally injected into the LPBN, induced ingestion of 0.3 M NaCl (14.3 ± 4.1 vs. saline: 0.2 ± 0.2 ml/210 min) and water (7.1 ± 2.9 vs. saline: 0.6 ± 0.5 ml/210 min). In cell-dehydrated rats, bilateral injections of baclofen (0.5 and 1.0 nmol/0.2 µl) into the LPBN induced an increase of 0.3 M NaCl intake (15.6 ± 5.7 and 21.5 ± 3.5 ml/210 min, respectively, vs. saline: 1.7 ± 0.8 ml/210 min) and an early inhibition of water intake (3.5 ± 1.4 and 6.7 ± 2.1 ml/150 min, respectively, vs. saline: 9.2 ± 1.4 ml/150 min). The pretreatment of the LPBN with 2-hydroxysaclofen (GABA(B) antagonist, 5 nmol/0.2 µl) potentiated the effect of baclofen on 0.3 M NaCl intake in the first 90 min of test and did not modify the inhibition of water intake induced by baclofen in cell-dehydrated rats. Baclofen injected into the LPBN did not affect blood pressure and heart rate. CONCLUSIONS: Thus, injection of baclofen into the LPBN in cell-dehydrated rats induced ingestion of 0.3 M NaCl and inhibition of water intake, suggesting that even in a hyperosmotic situation, the blockade of LPBN inhibitory mechanisms with baclofen is enough to drive rats to drink hypertonic NaCl, an effect independent of changes in blood pressure.


Assuntos
Baclofeno/farmacologia , Desidratação/psicologia , Agonistas GABAérgicos/farmacologia , Ponte/fisiologia , Solução Salina Hipertônica , Animais , Pressão Arterial/efeitos dos fármacos , Baclofeno/administração & dosagem , Baclofeno/análogos & derivados , Ingestão de Líquidos , Lateralidade Funcional/fisiologia , Agonistas GABAérgicos/administração & dosagem , Antagonistas GABAérgicos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Masculino , Concentração Osmolar , Ratos , Ratos Wistar
11.
Brain Res Bull ; 91: 31-7, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23291357

RESUMO

Alcohol use disorder is a compulsive behavior driven by motivational systems and by a poor control of consummatory behavior. The entopeduncular nucleus (EP) seems to be involved in the regulation of executive mechanisms, hence, in the expression of behavior. Endocannabinoids (eCB) are involved in alcohol intake mechanisms. The eCB receptor name cannabinoid receptor 1 (CB1R) is expressed in the EP in GABAergic terminals. The role of the eCB system (eCBs) of the EP in the modulation of alcohol seeking and intake behavior is unknown. Therefore, we decided to investigate the role of the eCBs and its interaction with GABA transmission in rat EP, in the regulation of alcohol intake behavior. Rats were submitted to a 10-day period of moderate alcohol (10% in tap water) ingestion. No tap water was available. On day 11, either anandamide (AEA, CB1 receptor agonist), AM251 (CB1R inverse agonist), baclofen (BAC, GABAB receptor agonist), or CGP35348 (GABAB receptor antagonist) was administered into the EP. One bottle of water and one of alcohol (10% in water) were available ad libitum for the following 24 h, and consumption was quantified at the end of this period. Results show that administration of AEA into the EP decreased alcohol consumption while AM251 and BAC administered independently increased alcohol consumption. AEA prevented the increase induced by AM251 or BAC. Likewise, CGP35348 prevented alcohol ingestion induced by AM251. These data suggest that eCBs dysfunction in the EP may be playing a crucial role in the abuse and dependence of alcohol and other drugs.


Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Alcoolismo/metabolismo , Endocanabinoides/metabolismo , Núcleo Entopeduncular/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Núcleo Entopeduncular/efeitos dos fármacos , Agonistas GABAérgicos/administração & dosagem , Antagonistas GABAérgicos/administração & dosagem , Injeções Intraventriculares , Masculino , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
12.
Neuropharmacology ; 64: 432-42, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22819624

RESUMO

A consolidated memory recalled by a specific reminder can become unstable (labile) and susceptible to facilitation or impairment for a discrete period of time. This labilization phase is followed by a process of stabilization called reconsolidation. The phenomenon has been shown in diverse types of memory, and different pharmacological agents have been used to disclose its presence. Several studies have revealed the relevance of the GABAergic system to this process. Consequently, our hypothesis is that the system is involved in the reconsolidation of declarative memory in humans. Thus, using our verbal learning task, we analyzed the effect of benzodiazepines on the re-stabilization of the declarative memory. On Day 1, volunteers learned an association between five cue- response-syllables. On Day 2, the verbal memory was labilized by a reminder presentation, and then a placebo capsule or 0.25 mg or 0.03 mg of clonazepam was administered to the subjects. The verbal memory was evaluated on Day 3. The volunteers who had received the 0.25 mg clonazepam along with the specific reminder on Day 2, exhibited memory improvement. In contrast, there was no effect when the drug was given without retrieval, when the memory was simply retrieved instead of being reactivated or when short-term memory testing was performed 4 h after reactivation. We discuss the GABAergic role in reconsolidation, which shows a collateral effect on other memories when the treatment is aimed at treating anxiety disorders. Further studies might elucidate the role of GABA in the reconsolidation process associated with dissimilar scenarios. This article is part of a Special Issue entitled 'Cognitive Enhancers'.


Assuntos
Clonazepam/farmacologia , Agonistas GABAérgicos/farmacologia , Memória/efeitos dos fármacos , Nootrópicos/farmacologia , Substâncias para Melhoria do Desempenho/farmacologia , Aprendizagem Verbal/efeitos dos fármacos , Adulto , Clonazepam/administração & dosagem , Sinais (Psicologia) , Relação Dose-Resposta a Droga , Feminino , Agonistas GABAérgicos/administração & dosagem , Humanos , Masculino , Memória de Longo Prazo/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Nootrópicos/administração & dosagem , Substâncias para Melhoria do Desempenho/administração & dosagem , Estudantes , Adulto Jovem
13.
Neurosci Lett ; 534: 188-92, 2013 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-23219800

RESUMO

Bilateral injections of the GABA(A) agonist muscimol into the lateral parabrachial nucleus (LPBN) disrupt satiety and induce strong ingestion of water and 0.3M NaCl in fluid-replete rats by mechanisms not completely clear. In the present study, we investigated the effects of the blockade of central muscarinic cholinergic receptors with atropine injected intracerebroventricularly (i.c.v.) on 0.3M NaCl and water intake induced by muscimol injections into the LPBN in fluid-replete rats. Male Holtzman rats with stainless steel cannulas implanted bilaterally into the LPBN and unilaterally into the lateral ventricle (LV) were used. Bilateral injections of muscimol (0.5nmol/0.2µL) into the LPBN induced 0.3M NaCl (32.2±9.9mL/4h, vs. saline: 0.4±0.2mL/4h) and water intake (11.4±4.4mL/4h, vs. saline: 0.8±0.4mL/4h) in fluid-replete rats previously treated with i.c.v. injection of saline. The previous i.c.v. injection of atropine (20nmol/1µL) reduced the effects of LPBN-muscimol on 0.3M NaCl (13.5±5.0mL/4h) and water intake (2.9±1.6mL/4h). The i.c.v. injection of atropine did not affect 0.3M NaCl (26.8±6.2mL/2h, vs. saline i.c.v.: 36.5±9.8mL/2h) or water intake (14.4±2.5mL/2h, vs. saline i.c.v.: 15.6±4.8mL/2h) in rats treated with furosemide+captopril subcutaneously combined with bilateral injections of moxonidine (α(2)-adrenoceptor/imidazoline agonist, 0.5nmol/0.2µL) into the LPBN, suggesting that the effect of atropine was not due to non-specific inhibition of ingestive behaviors. The results show that active central cholinergic mechanisms are necessary for the hypertonic NaCl and water intake induced by the blockade of the inhibitory mechanisms with injections of muscimol into the LPBN in fluid-replete rats. The suggestion is that in fluid-replete rats the action of LPBN mechanisms inhibits facilitatory signals produced by the activity of central cholinergic mechanisms to maintain satiety.


Assuntos
Ingestão de Alimentos/fisiologia , Ponte/metabolismo , Receptores de GABA-A/metabolismo , Receptores Muscarínicos/metabolismo , Cloreto de Sódio/metabolismo , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Atropina/farmacologia , Captopril/farmacologia , Diuréticos/farmacologia , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Furosemida/farmacologia , Agonistas GABAérgicos/farmacologia , Imidazóis/farmacologia , Injeções Intraventriculares , Losartan/farmacologia , Masculino , Antagonistas Muscarínicos/farmacologia , Muscimol/farmacologia , Ponte/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
14.
Pharmacol Biochem Behav ; 102(2): 233-40, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22579911

RESUMO

Baclofen, a GABA(B) agonist, reduces ethanol intake in animals and humans, but the contrary or no effect was also reported. Our previous study demonstrated that mice characterized as "loss of control over ethanol intake" had different Gabbr1 and Gabbr2 transcription levels, which express, respectively, the GABA(B1) and GABA(B2) subunits in brain areas related to addictive behavior. In the present study, we tested baclofen on ethanol intake in mice exposed to the free-choice paradigm. Adult male Swiss mice, individually housed, had free access to three bottles: ethanol (5% and 10%) and water. The protocol had four phases: acquisition (AC, 10 weeks), withdrawal (W, 4 cycles during 2 weeks of 2 day-free-choice and 2 day-only-water), reexposure (RE, 2 weeks), and adulteration of ethanol solutions with quinine (AD, 2 weeks). Mice characterized as "loss of control" (A, n=11, preference for ethanol in AC and maintenance of ethanol intake levels in AD), heavy (H, n=11, preference for ethanol in AC and reduction of ethanol intake levels in AD), and light (L, n=16, preference for water in all phases) drinkers were randomly distributed into two subgroups receiving either intraperitoneal injections of all doses of baclofen (1.25, 2.5, and 5.0mg/kg, given each dose twice in consecutive days) or saline, being exposed to free-choice. Fluid consumption was measured 24h later. Baclofen reduced ethanol intake in group L. In group H a reduction compared to AC was observed. Group A maintained their high ethanol intake even after baclofen treatment. Activation of the GABA(B) receptor depends on the precise balance between the GABA(B1) and GABA(B2) subunits, so the disproportionate transcription levels, we reported in group A, could explain this lack of response to baclofen. These data highlight the importance to test baclofen in individuals with different ethanol drinking profiles, including humans.


Assuntos
Consumo de Bebidas Alcoólicas , Baclofeno/farmacologia , Etanol/administração & dosagem , Agonistas GABAérgicos/farmacologia , Receptores de GABA-B/efeitos dos fármacos , Animais , Peso Corporal , Relação Dose-Resposta a Droga , Comportamento de Ingestão de Líquido , Masculino , Camundongos
15.
Behav Brain Res ; 232(1): 269-77, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22546523

RESUMO

Episodic memory refers to the recollection of what, where and when an event occurred. Computational models suggest that the dentate gyrus (DG) and the CA3 hippocampal subregions are involved in pattern separation and the rapid acquisition of episodes, while CA1 is involved in the formation of a temporal context. Most of the studies performed to test this hypothesis failed to simultaneously address the aspects of episodic memory. Recently, a new task of object recognition was validated in rats. In the first sample trial, the rat is exposed to four copies of an object. In second sample, the rat is exposed to four copies of a different object. In the test trial, two copies of each of the previous objects are presented. One copy of the object used in sample trial one is located in a different place, and it is expected to be the most explored. Our goal was to evaluate whether the pharmacological inactivation of the dorsal DG/CA3 and CA1 subregions could differentially impair the acquisition of the task. Inactivation of the DG/CA3 subregions impaired the spatial discrimination, while the temporal discrimination was preserved. Rats treated with muscimol in CA1 explored all the objects equally well, irrespective of place or presentation time. Our results are consistent with computational models that postulate a role for DG/CA3 in rapid encoding and in spatial pattern separation, and a role for CA1 in the in the formation of the temporal context of events and as well as in detecting spatial novelty.


Assuntos
Hipocampo/fisiologia , Memória Episódica , Percepção Espacial/fisiologia , Percepção do Tempo/fisiologia , Análise de Variância , Animais , Comportamento Animal/fisiologia , Região CA1 Hipocampal/anatomia & histologia , Região CA1 Hipocampal/fisiologia , Região CA3 Hipocampal/anatomia & histologia , Região CA3 Hipocampal/fisiologia , Interpretação Estatística de Dados , Comportamento Exploratório/fisiologia , Agonistas GABAérgicos/administração & dosagem , Agonistas GABAérgicos/farmacologia , Hipocampo/anatomia & histologia , Hipocampo/efeitos dos fármacos , Injeções , Masculino , Muscimol/administração & dosagem , Muscimol/farmacologia , Ratos , Ratos Long-Evans , Ratos Wistar , Percepção Espacial/efeitos dos fármacos , Técnicas Estereotáxicas , Percepção do Tempo/efeitos dos fármacos
16.
Behav Brain Res ; 232(1): 60-5, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22483998

RESUMO

GABAergic mechanisms in the preoptic region of the hypothalamus (POA) have been implicated in the generation and maintenance of NREM (quiet) sleep. We recently reported that neurons in the median peptic nucleus (MnPN) in the POA of the cat are selectively activated during NREM sleep. In the present study, we explored the hypothesis that NREM sleep is controlled by GABAergic mechanisms within the MnPN. Consequently, adult cats were utilized to determine GABA immunorreactivity within the MnPN and to examine the effects on sleep of the microinjection of a GABA(A) agonist (muscimol) and a GABA(A) antagonist (bicuculline) into this area. GABAergic neurons were present throughout the MnPN. Compared with control microinjections, after the application of muscimol, the time spent in NREM sleep (59.8±7.5 min) and REM sleep (6.9±4.7 min) decreased compared with control microinjections (103.8±5.2 and 20.2±4.3 min, respectively; P<0.005). In contrast, bicuculline microinjections increased only NREM sleep time (103.0±23.0 vs 77.7±23.7 min; P<0.05). These results demonstrate that GABAergic processes within the MnPN are involved in the generation and maintenance of sleep, especially NREM sleep.


Assuntos
GABAérgicos/farmacologia , Área Pré-Óptica/fisiologia , Sono/fisiologia , Ácido gama-Aminobutírico/fisiologia , Animais , Bicuculina/administração & dosagem , Bicuculina/farmacologia , Gatos , Interpretação Estatística de Dados , Eletroencefalografia/efeitos dos fármacos , Eletromiografia/efeitos dos fármacos , GABAérgicos/administração & dosagem , Agonistas GABAérgicos/administração & dosagem , Agonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/administração & dosagem , Antagonistas GABAérgicos/farmacologia , Neurônios GABAérgicos , Imuno-Histoquímica , Masculino , Microinjeções , Muscimol/administração & dosagem , Muscimol/farmacologia , Área Pré-Óptica/efeitos dos fármacos , Sono/efeitos dos fármacos , Sono REM/efeitos dos fármacos , Vigília/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo
17.
Brain Res ; 1448: 101-10, 2012 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-22405726

RESUMO

Previous evidence indicates that a balance between inhibitory gabaergic and excitatory angiotensinergic factors in the PVN is important for cardiovascular control. We investigated the cardiovascular response evoked from activation or blockade of GABA(A) receptors in the paraventricular nucleus (PVN), in transgenic rats with low brain angiotensinogen [TGR(ASrAOGEN)]. Brain Ang II and Ang-(1-7) levels were also determined. In functional experiments, TGR(ASrAOGEN) and Sprague-Dawley rats (SD, control) were anesthetized with urethane and blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were recorded. Brain Ang II and Ang-(1-7) levels were largely reduced in TGR(ASrAOGEN) compared with SD rats. Inhibition of PVN neurons with the GABA(A) agonist, muscimol (1 nmol/100 nL), resulted in an attenuated fall in all cardiovascular variables in TGR(ASrAOGEN) compared with SD rats. This difference was particularly pronounced in HR (TGR Mus -23±6 bpm vs. -77±9 bpm SD Mus; P<0.05) and RSNA (TGR -3±10% vs.-29±8% SD; P<0.05). Furthermore, the sympathetic response evoked by blockade of GABA(A) receptors in the PVN of TGR(ASrAOGEN) was also largely suppressed. The present data indicate that the sympathetic outflow mediated by PVN neurons under basal conditions is suppressed in TGR(ASrAOGEN) rats corroborating the functional significance of brain angiotensin production in the central regulation of sympathetic output to the cardiovascular system.


Assuntos
Angiotensinogênio/deficiência , Química Encefálica/efeitos dos fármacos , Agonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/farmacologia , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Receptores de GABA-A/fisiologia , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Química Encefálica/genética , Expressão Gênica/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Compostos de Hexametônio/farmacologia , Rim/inervação , Rim/fisiologia , Radioimunoensaio , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Sistema Nervoso Simpático/fisiologia , Transgenes/genética
18.
Neuropharmacology ; 62(1): 457-63, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21903111

RESUMO

Increasing evidence indicates that the medial prefrontal cortex (mPFC) and the amygdala mediate expression and extinction of conditioned fear, but few studies have examined the inputs to these structures. The dorsal part of the midline thalamus (dMT) contains structures such as the mediodorsal nucleus, paraventricular nucleus, and paratenial nucleus that project prominently to mPFC, as well as to basal (BA) and central (Ce) nuclei of the amygdala. Using temporary inactivation with GABA agonist muscimol, we found that dMT was necessary for retrieving auditory fear memory that was 24 h old, but not 2-8 h old. However, pre-training infusions did not impair fear acquisition or extinction. To determine the possible targets of dMT that might modulate fear retrieval, we combined dMT inactivation with Fos immunohistochemistry. Rats with inactivation-induced impairment in fear retrieval showed increased Fos in the lateral division of Ce (CeL), and decreased Fos in the medial division of Ce. No differences in Fos expression were observed in the mPFC or BA. We suggest that the projections from the paraventricular nucleus to CeL are involved in retrieval of well consolidated fear memories. This article is part of a Special Issue entitled 'Anxiety and Depression'.


Assuntos
Condicionamento Clássico/efeitos dos fármacos , Medo/psicologia , Rememoração Mental/fisiologia , Núcleos da Linha Média do Tálamo/fisiologia , Estimulação Acústica/efeitos adversos , Análise de Variância , Animais , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Agonistas GABAérgicos/farmacologia , Locomoção/efeitos dos fármacos , Masculino , Rememoração Mental/efeitos dos fármacos , Muscimol/farmacologia , Vias Neurais/fisiologia , Proteínas Oncogênicas v-fos/sangue , Proteínas Oncogênicas v-fos/metabolismo , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
19.
Neuroscience ; 199: 421-8, 2011 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-21964471

RESUMO

Glutamate and GABA are the main excitatory and inhibitory neurotransmitters in the CNS, and both may be involved in the neuronal dysfunction in neurodegenerative conditions. We have recently found that glutamate release was decreased in isolated synaptosomes from the rat cerebral cortex during the development of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. In contrast to control animals where GABA induced a decrease in the evoked glutamate release, which was abolished by picrotoxin (a GABA(A) antagonist), synaptosomes from EAE rats showed a loss in the inhibition of the glutamate release mediated by GABA with a concomitant diminution of the flunitrazepam-sensitive GABA(A) receptor density. We have presently further evaluated the relevance of the GABAergic system in EAE by treating rats challenged for the disease with the GABA agonist diazepam. Administration of diazepam during 6 days starting at day 6 or 11 after EAE active induction led to a marked decrease of the disease incidence and histological signs associated with the disease. Cellular reactivity and antibody responses against the encephalitogenic myelin basic protein were also diminished. Beyond the effects of diazepam on the autoimmune, inflammatory response, we report also a positive effect on neurotransmission. Treatment with diazepam inhibited the previously described reduction in glutamate release in the frontal cortex synaptosomes from EAE animals. These data suggest that an endogenous inhibitory GABAergic system within the immune system is involved in the diazepam effect on EAE and indicate that increasing GABAergic activity potently ameliorates EAE.


Assuntos
Autoimunidade/efeitos dos fármacos , Diazepam/farmacologia , Encefalomielite Autoimune Experimental/imunologia , Agonistas GABAérgicos/farmacologia , Inflamação/imunologia , Animais , Autoimunidade/imunologia , Encefalomielite Autoimune Experimental/patologia , Inflamação/patologia , Ratos , Ratos Wistar , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/imunologia , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/imunologia , Sinaptossomos/patologia
20.
Behav Brain Res ; 221(1): 75-82, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21377498

RESUMO

Baicalein (BA), one of the main flavonoids obtained from the Chinese medicinal herb Scutellaria baicalensis, usually exerts several pharmacological effects. In the central nervous system (CNS), BA exerts a protective effect on neurons against several neuronal insults among other effects, but it is not clear if this effect is due to its metabolite, baicalin. The purpose of the present study was to assess the anxiolytic-like and related properties of BA following its central administration (i.c.v.) in mice. BA (0.02, 0.2pmol) exerted an anxiolytic-like effect at low doses, increasing the time spent in open arms and the head-dipping whereas reducing the stretched-attend postures in the elevated plus-maze. BA also increased the duration of ether-induced sleep without affecting the pentylenetetrazol (PTZ)-induced convulsions. In addition, pretreatment with flumazenil (FMZ), PTZ, dehydroepiandrosterone sulfate (DHEAS), and dl-p-chlorophenilalanine ethyl ester (PCPA) were conducted in order to investigate its mechanism of action. PTZ and DHEAS, but not FMZ or PCPA, antagonized the BA's anxiolytic-like effect. Taken together our results showed that BA, when directly injected into the CNS, promotes anxiolytic-like and sedative effects, pharmacological activities dependent on GABAergic non-benzodiazepine sites but not on the 5-HT system.


Assuntos
Flavanonas/farmacologia , Agonistas GABAérgicos/farmacologia , Agonistas GABAérgicos/uso terapêutico , Antagonistas GABAérgicos/farmacologia , Convulsões/tratamento farmacológico , Sono/efeitos dos fármacos , Sono/fisiologia , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Sulfato de Desidroepiandrosterona/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Éter/farmacologia , Feminino , Fenclonina/análogos & derivados , Fenclonina/farmacologia , Flavanonas/administração & dosagem , Flavanonas/antagonistas & inibidores , Flavanonas/uso terapêutico , Flumazenil/farmacologia , Injeções Intraventriculares , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Pentilenotetrazol/farmacologia , Convulsões/induzido quimicamente
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