RESUMEN

Autism spectrum disorders (ASDs) are characterized by core behavioral symptoms in the domains of sociability, language/communication, and repetitive or stereotyped behaviors. Deficits in the prefrontal and hippocampal excitatory/inhibitory balance due to a functional loss of GABAergic interneurons are proposed to underlie these symptoms. Increasing the postsynaptic effects of GABA with compounds that selectively modulate GABAergic receptors could be a potential target for treating ASD symptoms. In addition, deficits in GABAergic interneurons have been linked to dopamine (DA) system dysregulation, and, despite conflicting evidence, abnormalities in the DA system activity may underly some ASD symptoms. Here, we investigated whether the positive allosteric modulator of α5-containing GABAA receptors (α5-GABAARs) SH-053-2'F-R-CH3 (10 mg/kg) attenuates behavioral abnormalities in rats exposed to valproic acid (VPA) in utero, an established risk factor for autism. We also evaluated if animals exposed to VPA in utero present changes in the ventral tegmental area (VTA) DA system activity using in vivo electrophysiology and if SH-053-2'F-R-CH3 could attenuate these changes. SH-053-2'F-R-CH3 was administered intraperitoneally 30 min before each behavioral test and electrophysiology. In utero VPA exposure caused male and female rats to present increased repetitive behavior (self-grooming) in early adolescence and deficits in social interaction in adulthood. Male, but not female VPA rats, also presented deficits in recognition memory as adults. SH-053-2'F-R-CH3 attenuated the impairments in sociability and cognitive function in male VPA-exposed rats without attenuating the decreased social interaction in females. Adult male and female VPA-exposed rats also showed an increased VTA DA neuron population activity, which was not changed by SH-053-2'F-R-CH3. Despite sex differences, our findings indicate that α5-GABAARs positive allosteric modulators may effectively attenuate some core ASD symptoms.

Asunto(s)

Efectos Tardíos de la Exposición Prenatal , Receptores de GABA-A , Conducta Social , Ácido Valproico , Animales , Femenino , Ácido Valproico/farmacología , Ratas , Masculino , Embarazo , Receptores de GABA-A/efectos de los fármacos , Dopamina/metabolismo , Trastorno del Espectro Autista/inducido químicamente , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/fisiopatología , Ratas Sprague-Dawley , Regulación Alostérica/efectos de los fármacos , Modelos Animales de Enfermedad , Conducta Animal/efectos de los fármacos , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/fisiopatología

RESUMEN

Anxiety is a commonly prevailing psychological disorder that requires effective treatment, wherein phytopharmaceuticals and nutraceuticals could offer a desirable therapeutic profile. Hybanthus enneaspermus (L.) F. Muell. is a powerful medicinal herb, reportedly effective against several ailments, including psychological disorders. The current research envisaged evaluating the anxiolytic potential of the ethanolic extract of Hybanthus enneaspermus (EEHE) and its toluene insoluble biofraction (ITHE) employing experimental and computational approaches. Elevated Plus Maze, Light and Dark Transition, Mirror Chamber, Hole board and Open field tests were used as screening models to assess the antianxiety potential of 100, 200 and 400 mg/kg body weight of EEHE and ITHE in rats subjected to social isolation, using Diazepam as standard. The brains of rats exhibiting significant anxiolytic activity were dissected for histopathological and biochemical studies. Antioxidant enzymes like catalase, superoxide dismutase, glutathione-S-transferase, glutathione peroxidase, glutathione reductase; and neurotransmitters viz. monoamines (serotonin, noradrenaline, dopamine), Gamma-aminobutyric acid (GABA), and glutamate were quantified in the different regions of rats' brain (cortex, hippocampus, pons, medulla oblongata, cerebellum). Chromatographic techniques were used to isolate phytoconstituents from the fraction exhibiting significant activity that were characterized by spectroscopic methods and subjected to in silico molecular docking. ITHE at 400 mg/kg body weight significantly mitigated anxiety in all the screening models (p < 0.05), reduced the inflammatory vacuoles and necrosis (p < 0.05) and potentiated the antioxidant enzymes (p < 0.05). It enhanced the monoamines and GABA levels while attenuating glutamate levels (p < 0.01) in the brain. Three significant flavonoids viz. Quercitrin, Rutin and Hesperidin were isolated from ITHE. In silico docking studies of these flavonoids revealed that the compounds exhibited substantial binding to the GABAA receptor. ITHE displayed a promising pharmacological profile in combating anxiety and modulating oxidative stress, attributing its therapeutic virtues to the flavonoids present.

Asunto(s)

Ansiolíticos , Ansiedad , Extractos Vegetales , Ratas Wistar , Animales , Ansiolíticos/farmacología , Ansiolíticos/aislamiento & purificación , Ansiolíticos/uso terapéutico , Ansiolíticos/química , Ratas , Extractos Vegetales/farmacología , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/uso terapéutico , Extractos Vegetales/química , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Masculino , Simulación del Acoplamiento Molecular , Receptores de GABA-A/metabolismo , Receptores de GABA-A/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos

RESUMEN

The reliable induction of long-term potentiation (LTP) in the dentate gyrus (DG) in vitro requires the blockade of the γ-aminobutyric acid A (GABAA) receptor. In these studies we examined the effectiveness of the specific GABAA receptor antagonist bicuculline methiodide (BMI) in facilitating LTP in the DG from hippocampal slices obtained from either C57Bl/6 mice or Sprague-Dawley rats, two species commonly used for electrophysiology. In the C57Bl/6 mice, maximal short-term potentiation and LTP in the DG were produced with a concentration of 5 µM BMI. In contrast, a concentration of 10 µM BMI was required to produce maximal short-term potentiation and LTP in the DG of Sprague-Dawley rats. These results reveal that there are species differences in the optimal amount of BMI required to produce robust and reliable LTP in the rodent DG in vitro and highlight the need to take consideration of the species being used when choosing concentrations of pharmacological agents to employ for electrophysiological use.NEW & NOTEWORTHY In this report we provide specific neurophysiological evidence for concentrations of GABAA antagonist required to study long-term potentiation in the medial perforant pathway of the dentate gyrus. Two commonly used species, Sprague-Dawley rats and C57Bl/6 mice, require different concentrations of bicuculline methiodide to induce optimal short-term and long-term potentiation.

Asunto(s)

Bicuculina , Giro Dentado , Antagonistas de Receptores de GABA-A , Potenciación a Largo Plazo , Ratones Endogámicos C57BL , Ratas Sprague-Dawley , Animales , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Giro Dentado/efectos de los fármacos , Giro Dentado/fisiología , Bicuculina/farmacología , Bicuculina/análogos & derivados , Antagonistas de Receptores de GABA-A/farmacología , Ratones , Ratas , Masculino , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/metabolismo , Receptores de GABA-A/fisiología , Especificidad de la Especie

RESUMEN

We previously showed that the PDE4 inhibitor apremilast reduces ethanol consumption in mice by protein kinase A (PKA) and GABAergic mechanisms. Preventing PKA phosphorylation of GABAA ß3 subunits partially blocked apremilast-mediated decreases in drinking. Here, we produced Gabrb1-S409A mice to render GABAA ß1 subunits resistant to PKA-mediated phosphorylation. Mass spectrometry confirmed the presence of the S409A mutation and lack of changes in ß1 subunit expression or phosphorylation at other residues. ß1-S409A male and female mice did not differ from wild-type C57BL/6J mice in expression of Gabrb1, Gabrb2, or Gabrb3 subunits or in behavioral characteristics. Apremilast prolonged recovery from ethanol ataxia to a greater extent in Gabrb1-S409A mice but prolonged recovery from zolpidem and propofol to a similar extent in both genotypes. Apremilast shortened recovery from diazepam ataxia in wild-type but prolonged recovery in Gabrb1-S409A mice. In wild-type mice, the PKA inhibitor H89 prevented apremilast modulation of ataxia by ethanol and diazepam, but not by zolpidem. In Gabrb1-S409A mice, inhibiting PKA or EPAC2 (exchange protein directly activated by cAMP) partially reversed apremilast potentiation of ethanol, diazepam, and zolpidem ataxia. Apremilast prevented acute tolerance to ethanol ataxia in both genotypes, but there were no genotype differences in ethanol consumption before or after apremilast. In contrast to results in Gabrb3-S408A/S409A mice, PKA phosphorylation of ß1-containing GABAA receptors is not required for apremilast's effects on acute tolerance or on ethanol consumption but is required for its ability to decrease diazepam intoxication. Besides PKA we identified EPAC2 as an additional cAMP-dependent mechanism by which apremilast regulates responses to GABAergic drugs.

Asunto(s)

Proteínas Quinasas Dependientes de AMP Cíclico , Etanol , Ratones Endogámicos C57BL , Inhibidores de Fosfodiesterasa 4 , Receptores de GABA-A , Talidomida , Animales , Talidomida/farmacología , Talidomida/análogos & derivados , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Inhibidores de Fosfodiesterasa 4/farmacología , Masculino , Femenino , Etanol/farmacología , Ratones , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Receptores de GABA-A/efectos de los fármacos , Técnicas de Sustitución del Gen , Fosforilación/efectos de los fármacos , Ataxia/genética , Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Consumo de Bebidas Alcohólicas/genética , Ratones Transgénicos , Diazepam/farmacología

RESUMEN

Zolpidem, a non-benzodiazepine hypnotic, is primarily used to treat insomnia. In a previous study, pior treatment with non-benzodiazepine receptor agonists was associated with inflammation. The present study aimed to clarify the association between the effects of zolpidem and inflammation in mice treated with lipopolysaccharide (LPS), a known model of inflammation. We assessed the zolpidem-induced loss of righting reflex (LORR) duration 24 h after LPS treatment in mice. Additionally, the expressions of γ-aminobutyric acid (GABA)A receptor subunit and K+-Cl- cotransporter isoform 2 (KCC2) mRNA in the hippocampus and frontal cortex were examined in LPS-treated mice. Pretreatment with LPS was associated with significantly prolonged duration of zolpidem-induced LORR compared to control mice. This effect was significantly attenuated by administering bicuculline, a GABAA receptor antagonist, or flumazenil, a benzodiazepine receptor antagonist, in LPS-treated mice. Compared to controls, LPS-treated mice showed no significant change in the expression of GABAA receptor subunits in the hippocampus or frontal cortex. Bumetanide, an Na+-K+-2Cl- cotransporter isoform 1 blocker, attenuated the extended duration of zolpidem-induced LORR observed in LPS-treated mice. LPS significantly decreased Kcc2 mRNA expression in the hippocampus and the frontal cortex. These findings suggest that inflammation increases zolpidem-induced LORR, possibly through a reduction in KCC2 expression.

Asunto(s)

Lipopolisacáridos , Piridinas , Receptores de GABA-A , Reflejo de Enderezamiento , Simportadores , Zolpidem , Animales , Zolpidem/farmacología , Ratones , Piridinas/farmacología , Masculino , Receptores de GABA-A/metabolismo , Receptores de GABA-A/efectos de los fármacos , Simportadores/genética , Simportadores/metabolismo , Reflejo de Enderezamiento/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Cotransportadores de K Cl , Hipnóticos y Sedantes/farmacología , Inflamación/inducido químicamente , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo

RESUMEN

OBJECTIVES: To investigate roles of brain carbon monoxide (CO), an endogenous gasotransmitter, in regulation of the rat micturition reflex. METHODS: In urethane-anesthetized (0.8 g/kg, ip) male rats, evaluation of urodynamic parameters was started 1 h before intracerebroventricular administration of CORM-3 (CO donor) or ZnPP (non-selective inhibitor of heme oxygenase, a CO producing enzyme) and continued for 2 h after the administration. We also investigated effects of centrally pretreated SR95531 (GABAA receptor antagonist) or SCH50911 (GABAB receptor antagonist) on the CORM-3-induced response. RESULTS: CORM-3 significantly prolonged intercontraction intervals (ICIs) without changing maximal voiding pressure (MVP), while ZnPP significantly shortened ICI and reduced single-voided volume and bladder capacity without affecting MVP, post-voided residual volume, or voiding efficiency. The ZnPP-induced ICI shortening was reversed by CORM-3. The CORM-3-induced ICI prolongation was significantly attenuated by centrally pretreated SR95531 or SCH50911, respectively. CONCLUSIONS: Brain CO can suppress the rat micturition reflex through brain γ-aminobutyric acid (GABA) receptors.

Asunto(s)

Encéfalo , Monóxido de Carbono , Ratas Sprague-Dawley , Vejiga Urinaria , Micción , Animales , Masculino , Micción/efectos de los fármacos , Ratas , Monóxido de Carbono/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/fisiología , Reflejo/efectos de los fármacos , Compuestos Organometálicos/farmacología , Hemo Oxigenasa (Desciclizante)/metabolismo , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Urodinámica/efectos de los fármacos , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/metabolismo , Receptores de GABA/efectos de los fármacos , Receptores de GABA/metabolismo

RESUMEN

There is a critical need for safer and better-tolerated alternatives to address the current limitations of antidepressant treatments for major depressive disorder. Recently, drugs targeting the GABA system via α5-containing GABAA receptors (α5-GABAAR) as negative allosteric modulators (α5-NAMs) have shown promise in alleviating stress-related behaviors in preclinical studies, suggesting that α5-NAMs may have translational relevance as novel antidepressant medications. Here, we evaluated the efficacy of Basmisanil, an α5-NAM that has been evaluated in Phase 2 clinical studies as a cognitive enhancer, in a battery of behavioral tests relevant to coping strategies, motivation, and aversion in male mice, along with plasma and brain pharmacokinetic measurements. Our findings reveal that Basmisanil induces dose-dependent rapid antidepressant-like responses in the forced swim test and sucrose splash test without promoting locomotor stimulating effects. Furthermore, Basmisanil elicits sustained behavioral responses in the female urine sniffing test and sucrose splash test, observed 24 h and 48 h post-treatment, respectively. Bioanalysis of plasma and brain samples confirms effective blood-brain barrier penetration by Basmisanil and extrapolation to previously published data suggest that effects were observed at doses (10 and 30 mg/kg i.p.) corresponding to relatively modest levels of α5-GABAAR occupancy (40-65 %). These results suggest that Basmisanil exhibits a combination of rapid and sustained antidepressant-like effects highlighting the potential of α5-NAMs as a novel therapeutic strategy for depression.

Asunto(s)

Antidepresivos , Receptores de GABA-A , Animales , Masculino , Receptores de GABA-A/metabolismo , Receptores de GABA-A/efectos de los fármacos , Antidepresivos/farmacología , Antidepresivos/farmacocinética , Ratones , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Femenino , Conducta Animal/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Ratones Endogámicos C57BL

RESUMEN

BACKGROUND: GABA, a key inhibitory neurotransmitter, has synaptic and extrasynaptic receptors on the postsynaptic neuron. Background GABA, which spills over from the synaptic cleft, acts on extrasynaptic delta subunit containing GABAA receptors. The role of extrasynaptic GABAergic input in migraine is unknown. We investigated the susceptibility to valid migraine-provoking substances with clinically relevant behavioral readouts in Genetic Absence Epilepsy of Rats Strasbourg (GAERS), in which the GABAergic tonus was altered. Subsequently, we screened relevant GABAergic mechanisms in Wistar rats by pharmacological means to identify the mechanisms. METHODS: Wistar and GAERS rats were administered nitroglycerin (10 mg/kg) or levcromakalim (1 mg/kg). Mechanical allodynia and photophobia were assessed using von Frey monofilaments and a dark-light box. Effects of GAT-1 blocker tiagabine (5 mg/kg), GABAB receptor agonist baclofen (2 mg/kg), synaptic GABAA receptor agonist diazepam (1 mg/kg), extrasynaptic GABAA receptor agonists gaboxadol (4 mg/kg), and muscimol (0.75 mg/kg), T-type calcium channel blocker ethosuximide (100 mg/kg) or synaptic GABAA receptor antagonist flumazenil (15 mg/kg) on levcromakalim-induced migraine phenotype were screened. RESULTS: Unlike Wistar rats, GAERS exhibited no reduction in mechanical pain thresholds or light aversion following nitroglycerin or levcromakalim injection. Ethosuximide did not reverse the resistant phenotype in GAERS, excluding the role of T-type calcium channel dysfunction in this phenomenon. Tiagabine prevented levcromakalim-induced mechanical allodynia in Wistar rats, suggesting a key role in enhanced GABA spillover. Baclofen did not alleviate mechanical allodynia. Diazepam failed to mitigate levcromakalim-induced migraine phenotype. Additionally, the resistant phenotype in GAERS was not affected by flumazenil. Extrasynaptic GABAA receptor agonists gaboxadol and muscimol inhibited periorbital allodynia in Wistar rats. CONCLUSION: Our study introduced a rat strain resistant to migraine-provoking agents and signified a critical involvement of extrasynaptic δGABAergic receptors. Extrasynaptic δ GABAA receptors, by mediating constant background inhibition on the excitability of neurons, stand as a novel drug target with a therapeutic potential in migraine.

Asunto(s)

Trastornos Migrañosos , Fenotipo , Ratas Wistar , Receptores de GABA-A , Animales , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/fisiopatología , Ratas , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/metabolismo , Masculino , Modelos Animales de Enfermedad , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Epilepsia Tipo Ausencia/tratamiento farmacológico , Epilepsia Tipo Ausencia/fisiopatología , Nitroglicerina/farmacología , Nitroglicerina/toxicidad , Fotofobia/etiología , Fotofobia/fisiopatología

RESUMEN

OBJECTIVE: North Sea Progressive Myoclonus Epilepsy (NS-PME) is a rare genetic disorder characterized by ataxia, myoclonus and seizures with a progressive course. Although the cause of NS-PME is known, namely a homozygous mutation in the GOSR2 gene (c.430 G>T; p. Gly144Trp), sufficient treatment is lacking. Despite combinations of on average 3-5 anti-seizure medications (ASMs), debilitating myoclonus and seizures persist. Here we aimed to gain insight into the most effective anti-convulsive target in NS-PME by evaluating the individual effects of ASMs in a NS-PME Drosophila model. METHOD: A previously generated Drosophila model for NS-PME was used displaying progressive heat-sensitive seizures. We used this model to test 1. a first-generation ASM (sodium barbital), 2. common ASMs used in NS-PME (clonazepam, valproic acid, levetiracetam, ethosuximide) and 3. a novel third-generation ASM (ganaxolone) with similar mode of action to sodium barbital. Compounds were administered by adding them to the food in a range of concentrations. After 7 days of treatment, the percentage of heat-induced seizures was determined and compared to non-treated but affected controls. RESULTS: As previously reported in the NS-PME Drosophila model, sodium barbital resulted in significant seizure suppression, with increasing effect at higher dosages. Of the commonly prescribed ASMs, clonazepam and ethosuximide resulted in significant seizure suppression, whereas both valproic acid and levetiracetam did not show any changes in seizures. Interestingly, ganaxolone did result in seizure suppression as well. CONCLUSION: Of the six drugs tested, three of the four that resulted in seizure suppression (sodium barbital, clonazepam, ganaxolone) are primary known for their direct effect on GABAA receptors. This suggests that GABAA could be a potentially important target in the treatment of NS-PME. Consequently, these findings add rationale to the exploration of the clinical effect of ganaxolone in NS-PME and other progressive myoclonus epilepsies.

Asunto(s)

Anticonvulsivantes , Modelos Animales de Enfermedad , Drosophila , Epilepsias Mioclónicas Progresivas , Animales , Anticonvulsivantes/uso terapéutico , Anticonvulsivantes/farmacología , Epilepsias Mioclónicas Progresivas/genética , Epilepsias Mioclónicas Progresivas/tratamiento farmacológico , Animales Modificados Genéticamente , Receptores de GABA-A/genética , Receptores de GABA-A/efectos de los fármacos

RESUMEN

Objective: To investigate the molecular mechanism of sevoflurane affecting the development of the offspring's nervous system through the GABAAR/Sirt 1 pathway. Methods: Pregnant rats were obtained by mating females and males, and were randomly divided into 3 h sevoflurane (2.3% sevoflurane anesthesia for 3 h), 6 h sevoflurane (2.3% sevoflurane anesthesia for 6 h), Sirt-1 activator-SRT1720 (10 mg/kg SRT1720), 6 h sevoflurane+SRT1720 (10 mg/kg SRT1720) and control groups) group and control group, 31-day-old littermates were taken out and their learning and memory functions were examined by the water maze experiment; the heads were severed to remove the brains, and the kits were used to detect the levels of 5-HT and Ach in the brain tissue; the hippocampal tissues of the littermates were isolated, and neuronal damage in the hippocampal tissues was assessed by Nissen staining; neuronal apoptosis in the hippocampal tissues was detected by TUNEL staining; and GABAAR in the hippocampal tissues was detected by Western blot. GABAAR, Sirt-1, and apoptosis-related proteins (Caspase-3, BCL-2, BAX) in hippocampal tissue. Results: Compared with the control group, the 3 h sevoflurane group and the 6 h sevoflurane group neurons were arranged sparsely, the cells appeared to be swollen, the evasion latency, the apoptosis rate of neurons, the expression of Caspase-3, and BAX increased significantly, and the number of crossing the plateau, the level of 5-HT and Ach in the brain tissues, and the expression of GABAAR, Sirt-1, and BCL-2 were decreased significantly, and the differences existed between the groups (P < .5); compared with the 6 h sevoflurane group, neuronal morphological changes in the hippocampal tissue of the 6 h sevoflurane+SRT1720 group were improved, with a significant decrease in the evasion latency, neuronal apoptosis rate, expression of Caspase-3 and BAX, and a significant increase in the number of traversing platforms, brain tissue 5-HT, Ach level, GABAAR, Sirt-1, and BCL-2 expression (P < .5); compared with the SRT1720 group, the neurons in the 6 h sevoflurane + SRT1720 group were sparsely arranged, with a significant increase in evasion latency, neuronal apoptosis rate, caspase-3, BAX expression, and a significant decrease in the number of traversing platforms, brain tissue 5-HT, Ach level, GABAAR, Sirt-1, and BCL-2 expression (P < .5 ). Conclusion: Sevoflurane can affect the neurological development of rat offspring, which may be related to the inhibition of Sirt-1 expression.

Asunto(s)

Sevoflurano , Sirtuina 1 , Sevoflurano/farmacología , Animales , Sirtuina 1/metabolismo , Ratas , Femenino , Embarazo , Anestésicos por Inhalación/farmacología , Receptores de GABA-A/metabolismo , Receptores de GABA-A/efectos de los fármacos , Masculino , Ratas Sprague-Dawley , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Apoptosis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos

RESUMEN

BACKGROUND: Dysfunctional sensory gating in anxiety disorders, indexed by the failure to inhibit the P50 event-related potential (ERP) to repeated stimuli, has been linked to deficits in the major inhibitory neurotransmitter γ-aminobutyric acid (GABA). AIMS/METHODS: This study, conducted in 30 healthy volunteers, examined the acute effects of GABAA (lorazepam: 1 mg) and GABAB receptor (baclofen: 10 mg) agonists on P50 measures of auditory sensory gating within a paired-stimulus (S1-S2) paradigm and assessed changes in gating in relation to self-ratings of anxiety. RESULTS: Compared to placebo, lorazepam reduced ERP indices of sensory gating by attenuating response to S1. Although not directly impacting P50 inhibition, baclofen-induced changes in gating (relative to placebo) were negatively correlated with trait but not state anxiety. CONCLUSIONS: These preliminary findings support the involvement of GABA in sensory gating and tentatively suggest a role for GABAB receptor signaling in anxiety-associated gating dysregulation.

Asunto(s)

Ansiedad , Baclofeno , Agonistas de Receptores GABA-B , Lorazepam , Receptores de GABA-B , Filtrado Sensorial , Humanos , Masculino , Femenino , Adulto , Baclofeno/farmacología , Lorazepam/farmacología , Agonistas de Receptores GABA-B/farmacología , Ansiedad/metabolismo , Adulto Joven , Filtrado Sensorial/efectos de los fármacos , Receptores de GABA-B/metabolismo , Receptores de GABA-B/efectos de los fármacos , Agonistas de Receptores de GABA-A/farmacología , Voluntarios Sanos , Método Doble Ciego , Potenciales Evocados Auditivos/efectos de los fármacos , Potenciales Evocados Auditivos/fisiología , Receptores de GABA-A/metabolismo , Receptores de GABA-A/efectos de los fármacos , Adolescente

RESUMEN

Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by α5 subunit-containing γ-aminobutyric acid type A receptors. By Caraiscos VB, Elliott EM, You-Ten KE, Cheng VY, Belelli D, Newell JG, Jackson MF, Lambert JJ, Rosahl TW, Wafford KA, MacDonald JF, Orser BA. Proc Natl Acad Sci U S A 2004; 101:3662-7. Reprinted with permission. In this Classic Paper Revisited, the author recounts the scientific journey leading to a report published in the Proceedings of the National Academy of Sciences (PNAS) and shares several personal stories from her formative years and "research truths" that she has learned along the way. Briefly, the principal inhibitory neurotransmitter in the brain, γ-aminobutyric acid (GABA), was conventionally thought to regulate cognitive processes by activating synaptic GABA type A (GABAA) receptors and generating transient inhibitory synaptic currents. However, the author's laboratory team discovered a novel nonsynaptic form of tonic inhibition in hippocampal pyramidal neurons, mediated by extrasynaptic GABAA receptors that are pharmacologically distinct from synaptic GABAA receptors. This tonic current is highly sensitive to most general anesthetics, including sevoflurane and propofol, and likely contributes to the memory-blocking properties of these drugs. Before the publication in PNAS, the subunit composition of GABAA receptors that generate the tonic current was unknown. The team's research showed that GABAA receptors containing the α5 subunit (α5GABAARs) generated the tonic inhibitory current in hippocampal neurons. α5GABAARs are highly sensitive to GABA, desensitize slowly, and are thus well suited for detecting low, persistent, ambient concentrations of GABA in the extracellular space. Interest in α5GABAARs has surged since the PNAS report, driven by their pivotal roles in cognitive processes and their potential as therapeutic targets for treating various neurologic disorders.

Asunto(s)

Receptores de GABA-A , Animales , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/metabolismo , Ratones , Células Piramidales/efectos de los fármacos , Células Piramidales/fisiología , Células Piramidales/metabolismo , Humanos , Sinapsis/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ácido gamma-Aminobutírico/metabolismo

RESUMEN

In this study, the electrophysiological and biochemical consequences of repeated exposure to morphine in male rats on glutamatergic synaptic transmission, synaptic plasticity, the expression of GABA receptors and glutamate receptors at the temporoammonic-CA1 synapse along the longitudinal axis of the hippocampus (dorsal, intermediate, ventral, DH, IH, VH, respectively) were investigated. Slice electrophysiological methods, qRT-PCR, and western blotting techniques were used to characterize synaptic plasticity properties. We showed that repeated morphine exposure (RME) reduced excitatory synaptic transmission and ability for long-term potentiation (LTP) in the VH as well as eliminated the dorsoventral difference in paired-pulse responses. A decreased expression of NR2B subunit in the VH and an increased expression GABAA receptor of α1 and α5 subunits in the DH were observed following RME. Furthermore, RME did not affect the expression of NR2A, AMPA receptor subunits, and γ2GABAA and GABAB receptors in either segment of the hippocampus. In sum, the impact of morphine may differ depending on the region of the hippocampus studied. A distinct change in the short- and long-term synaptic plasticity along the hippocampus long axis due to repeated morphine exposure, partially mediated by a change in the expression profile of glutamatergic receptor subunits. These findings can be useful in further understanding the cellular mechanism underlying deficits in information storage and, more generally, cognitive processes resulting from chronic opioid abuse.

Asunto(s)

Morfina , Plasticidad Neuronal , Ratas Sprague-Dawley , Animales , Masculino , Morfina/farmacología , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/metabolismo , Ratas , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Narcóticos/farmacología , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Receptores de GABA-A/metabolismo , Receptores de GABA-A/efectos de los fármacos , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Receptores de GABA/metabolismo , Receptores de GABA/efectos de los fármacos

RESUMEN

Dimdazenil (Junoenil®) is a small-molecule, oral, partial positive allosteric modulator of the gamma-aminobutyric acid (GABA)A receptor that is being developed by Zhejiang Jingxin Pharmaceutical in collaboration with Evotec for the treatment of insomnia. Dimdazenil is designed to overcome issues associated with full GABAA receptor agonists, such as tolerance, withdrawal symptoms and associated adverse effects. On 29 November 2023, dimdazenil oral capsules received approval in China for the short-term treatment of insomnia. This article summarizes the milestones in the development of dimdazenil leading to this first approval for insomnia.

Asunto(s)

Aprobación de Drogas , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , China , Moduladores del GABA/farmacología , Moduladores del GABA/uso terapéutico , Moduladores del GABA/efectos adversos , Moduladores del GABA/administración & dosificación , Receptores de GABA-A/metabolismo , Receptores de GABA-A/efectos de los fármacos , Administración Oral , Flumazenil/farmacología , Flumazenil/uso terapéutico

RESUMEN

Acid-sensing ion channels (ASICs) are proton-gated ion channels that mediate nociception in the peripheral nervous system and contribute to fear and learning in the central nervous system. Sevanol was reported previously as a naturally-occurring ASIC inhibitor from thyme with favorable analgesic and anti-inflammatory activity. Using electrophysiological methods, we found that in the high micromolar range, the compound effectively inhibited homomeric ASIC1a and, in sub- and low-micromolar ranges, positively modulated the currents of α1ß2γ2 GABAA receptors. Next, we tested the compound in anxiety-related behavior models using a targeted delivery into the hippocampus with parallel electroencephalographic measurements. In the open field, 6 µM sevanol reduced both locomotor and θ-rhythmic activity similar to GABA, suggesting a primary action on the GABAergic system. At 300 µM, sevanol markedly suppressed passive avoidance behavior, implying alterations in conditioned fear memory. The observed effects could be linked to distinct mechanisms involving GABAAR and ASIC1a. These results elaborate the preclinical profile of sevanol as a candidate for drug development and support the role of ASIC channels in fear-related functions of the hippocampus.

Asunto(s)

Thymus (Planta) , Canales Iónicos Sensibles al Ácido , Miedo/efectos de los fármacos , Ácido gamma-Aminobutírico , Hipocampo/efectos de los fármacos , Receptores de GABA-A/efectos de los fármacos , Thymus (Planta)/química

RESUMEN

Type A γ-aminobutyric acid receptors (GABAARs) are the principal inhibitory receptors in the brain and the target of a wide range of clinical agents, including anaesthetics, sedatives, hypnotics and antidepressants1-3. However, our understanding of GABAAR pharmacology has been hindered by the vast number of pentameric assemblies that can be derived from 19 different subunits4 and the lack of structural knowledge of clinically relevant receptors. Here, we isolate native murine GABAAR assemblies containing the widely expressed α1 subunit and elucidate their structures in complex with drugs used to treat insomnia (zolpidem (ZOL) and flurazepam) and postpartum depression (the neurosteroid allopregnanolone (APG)). Using cryo-electron microscopy (cryo-EM) analysis and single-molecule photobleaching experiments, we uncover three major structural populations in the brain: the canonical α1ß2γ2 receptor containing two α1 subunits, and two assemblies containing one α1 and either an α2 or α3 subunit, in which the single α1-containing receptors feature a more compact arrangement between the transmembrane and extracellular domains. Interestingly, APG is bound at the transmembrane α/ß subunit interface, even when not added to the sample, revealing an important role for endogenous neurosteroids in modulating native GABAARs. Together with structurally engaged lipids, neurosteroids produce global conformational changes throughout the receptor that modify the ion channel pore and the binding sites for GABA and insomnia medications. Our data reveal the major α1-containing GABAAR assemblies, bound with endogenous neurosteroid, thus defining a structural landscape from which subtype-specific drugs can be developed.

Asunto(s)

Microscopía por Crioelectrón , Neuroesteroides , Receptores de GABA-A , Ácido gamma-Aminobutírico , Animales , Ratones , Sitios de Unión/efectos de los fármacos , Depresión Posparto/tratamiento farmacológico , Flurazepam/farmacología , Ácido gamma-Aminobutírico/metabolismo , Hipnóticos y Sedantes/farmacología , Activación del Canal Iónico/efectos de los fármacos , Neuroesteroides/metabolismo , Neuroesteroides/farmacología , Fotoblanqueo , Pregnanolona/farmacología , Conformación Proteica/efectos de los fármacos , Subunidades de Proteína/química , Subunidades de Proteína/efectos de los fármacos , Subunidades de Proteína/metabolismo , Receptores de GABA-A/química , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/metabolismo , Receptores de GABA-A/ultraestructura , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Zolpidem/farmacología

RESUMEN

Animals need to cope with abundant sensory information, and one strategy is to selectively direct attention to only the most relevant part of the environment. Although the cortical networks of selective attention have been studied extensively, its underlying neurotransmitter systems, especially the role of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), remain less well understood. Increased GABAA receptor activity because of administration of benzodiazepines such as lorazepam is known to slow reactions in cognitive tasks. However, there is limited knowledge about GABAergic involvement in selective attention. Particularly, it is unknown whether increased GABAA receptor activity slows the build-up of selectivity or generally widens attentional focus. To address this question, participants (n = 29) received 1 mg lorazepam and placebo (within-subjects, double-blind) and performed an extended version of the flanker task. The spatial distribution of selective attention was studied by systematically manipulating number and position of incongruent flankers; the temporal build-up was characterized using delta plots. An online task version was presented to an independent, unmedicated sample (n = 25) to verify task effects. Under placebo and in the unmedicated sample, only the number of incongruent flankers, but not their position, influenced RTs. Incongruent flankers impaired RTs more strongly under lorazepam than placebo, especially when adjacent to the target. Delta plot analyses of RT showed that this effect persisted even when participants reacted slowly, indicating that lorazepam-induced impairments in selective attention do not result from simply slowed down build-up of selectivity. Instead, our data indicate that increased GABAA receptor activity widens the attentional focus.

Asunto(s)

Atención , Moduladores del GABA , Receptores de GABA-A , Método Doble Ciego , Lorazepam/farmacología , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/metabolismo , Humanos , Atención/efectos de los fármacos , Atención/fisiología , Moduladores del GABA/farmacología

RESUMEN

Background/aim: Propofol is a positive allosteric modulator of GABAA receptor (GABAAR) and has potent antioxidant activity. The aim of this study was to investigate the effect of propofol on damage to the cerebral cortex and hippocampus in a lithium chloride (LiCl)-pilocarpine animal model of status epilepticus (SE). Materials and methods: Adult male Sprague Dawley rats were injected with LiCl-pilocarpine to induce SE. They were then randomized and injected 30 min later with vehicle saline (SE+saline), propofol (SE+PPF, 50 mg/kg), Diazepam (SE+DZP, 10 mg/kg), Scopolamine (SE+SCOP, 10 mg/kg), or MK-801 (SE+MK-801, 2 mg/kg). Another group of rats received saline only and served as the naïve control (BLK). The levels of superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA) in the serum, cortex and hippocampus were analyzed 2 and 24 h posttreatment. The degree of tissue damage in the cortex and hippocampus of individual rats was assessed 24 h posttreatment, together with expression of the GABAAR α1 subunit. Results: The propofol group showed reduced levels of tissue damage in the cerebral cortex and hippocampus, decreased levels of MDA, and increased levels of GSH compared to the SE+saline group. No changes in SOD level were observed in serum and tissue samples from the cortex and hippocampus of SE+saline rats. Immunohistochemistry and Western blot assays showed that propofol treatment significantly increased the expression of GABAAR α1 subunit in the cortical and hippocampal tissues of SE rats. Conclusion: Propofol treatment protected against SE-induced tissue injury in the cortex and hippocampus of rats. This was due at least in part to its antioxidant activity and to its induction of GABAAR α1 subunit expression in the brain.

Asunto(s)

Modelos Animales de Enfermedad , Cloruro de Litio , Estrés Oxidativo , Pilocarpina , Propofol , Ratas Sprague-Dawley , Receptores de GABA-A , Estado Epiléptico , Animales , Propofol/farmacología , Receptores de GABA-A/metabolismo , Receptores de GABA-A/efectos de los fármacos , Estado Epiléptico/inducido químicamente , Estado Epiléptico/metabolismo , Estado Epiléptico/tratamiento farmacológico , Pilocarpina/toxicidad , Masculino , Cloruro de Litio/farmacología , Estrés Oxidativo/efectos de los fármacos , Ratas , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/inducido químicamente , Malondialdehído/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/efectos de los fármacos

RESUMEN

Background and Aims: A third of patients with primary biliary cholangitis (PBC) experience poorly understood cognitive symptoms, with a significant impact on quality of life (QOL), and no effective medical treatment. Allopregnanolone, a neurosteroid, is a positive allosteric modulator of gamma-aminobutyricacid-A (GABA-A) receptors, associated with disordered mood, cognition, and memory. This study explored associations between allopregnanolone and a disease-specific QOL scoring system (PBC-40) in PBC patients. Method: Serum allopregnanolone levels were measured in 120 phenotyped PBC patients and 40 age and gender-matched healthy controls. PBC subjects completed the PBC-40 at recruitment. Serum allopregnanolone levels were compared across PBC-40 domains for those with none/mild symptoms versus severe symptoms. Results: There were no overall differences in allopregnanolone levels between healthy controls (median = 0.03 ng/ml (IQR = 0.025)) and PBC patients (0.031 (0.42), p = 0.42). Within the PBC cohort, higher allopregnanolone levels were observed in younger patients (r (120) = -0.53, p < 0.001) but not healthy controls (r (39) = -0.21, p = 0.21). Allopregnanolone levels were elevated in the PBC-40 domains, cognition (u = 1034, p = 0.02), emotional (u = 1374, p = 0.004), and itch (u = 795, p = 0.03). Severe cognitive symptoms associated with a younger age: severe (50 (12)) vs. none (60 (13); u = 423 p = 0.001). Conclusion: Elevated serum allopregnanolone is associated with severe cognitive, emotional, and itch symptoms in PBC, in keeping with its known action on GABA-A receptors. Existing novel compounds targeting allopregnanolone could offer new therapies in severely symptomatic PBC, satisfying a significant unmet need.

Asunto(s)

Cirrosis Hepática Biliar , Neuroesteroides , Receptores de GABA-A , Humanos , Cirrosis Hepática Biliar/complicaciones , Cirrosis Hepática Biliar/tratamiento farmacológico , Neuroesteroides/farmacología , Neuroesteroides/uso terapéutico , Pregnanolona/farmacología , Pregnanolona/uso terapéutico , Calidad de Vida , Receptores de GABA-A/efectos de los fármacos

RESUMEN

CONTEXT: The sleep-promoting activity of Nelumbo nucifera Gaertn. (Nymphaeaceae) alkaloids in leaves or seeds are well known. However, the sleep-promoting activity of the lotus rhizome (LE), which is used mainly as food, has not yet been evaluated. OBJECTIVE: We investigated the sleep-promoting activity of LE water extract. MATERIALS AND METHODS: Institute of Cancer Research (ICR) mice (n = 8) were subject to a pentobarbital-induced sleep test to assess changes in sleep latency and duration following the administration of LE (80-150 mg/kg). In addition, electroencephalography analysis was performed to determine the sleep quality after LE treatment as well as the sleep recovery effect of LE using a caffeine-induced insomnia SD rat model. Real-time PCR and western blot analysis were performed to investigate the expression of neurotransmitter receptors, and the GABAA receptor antagonists were used for receptor binding analysis. RESULTS: An oral administration of 150 mg/kg LE significantly increased sleep duration by 24% compared to the control. Furthermore, LE increased nonrapid eye movement (NREM) sleep by increasing theta and delta powers. In the insomnia model, LE increased sleep time by increasing NREM sleep. Moreover, treatment with picrotoxin and flumazenil decreased the sleep time by 33% and 23%, respectively, indicating an involvement of the GABAA receptor in the sleep-enhancing activity of LE. The expression of GABAA receptors and the concentration of GABA in the brain were increased by LE. DISCUSSION AND CONCLUSIONS: The results suggest that the sleep-promoting activity of LE was via the GABAA receptor. Collectively, these data show that LE may promote sleep.

Asunto(s)

Lotus , Nelumbo , Extractos Vegetales , Receptores de GABA-A , Trastornos del Inicio y del Mantenimiento del Sueño , Animales , Ratones , Nelumbo/metabolismo , Extractos Vegetales/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/metabolismo , Rizoma/química , Sueño/efectos de los fármacos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Agua/farmacología , Ácido gamma-Aminobutírico/farmacología