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1.
Pharmacopsychiatry ; 56(4): 154-161, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37220781

RESUMO

INTRODUCTION: There is a need for novel anxiolytics with improved side effect profiles compared to benzodiazepines. A promising candidate with alternative pharmacodynamics is the translocator protein ligand, etifoxine. METHODS: To get further insight into its mechanisms of action and side effects compared to the benzodiazepine alprazolam, we performed a double-blind, placebo-controlled, repeated-measures study in 36 healthy male subjects. Participants were examined for trait anxiety and side effects and underwent repeated transcranial magnetic stimulation (TMS) assessments, including motor evoked potentials (MEP), short intracortical inhibition (SICI), intracortical facilitation (ICF), and cortical silent period (CSP). RESULTS: We observed attenuation of MEPs by alprazolam but not by etifoxine. SICI was not significantly affected by alprazolam or etifoxine. However, the response pattern indicated a lowered SICI threshold after the administration of etifoxine and alprazolam compared to the placebo. ICF and CSP were influenced by neither medication. Alprazolam led to higher sedation and subjective impairment of concentration compared to etifoxine. Individual anxiety trait scores did not affect TMS parameters. DISCUSSION: This study indicated a favorable side effect profile of etifoxine in healthy volunteers. Moreover, it revealed differential GABA-related effects on neuromuscular function by means of TMS. The side effects and TMS profile of etifoxine are compatible with the involvement of neurosteroidogenesis and a predominant α3 subunit modulation compared to alprazolam.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Córtex Motor , Humanos , Masculino , Alprazolam/farmacologia , Estimulação Magnética Transcraniana , Córtex Motor/fisiologia , GABAérgicos/farmacologia
2.
J Neurosci ; 43(13): 2305-2325, 2023 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-36813575

RESUMO

Cholecystokinin (CCK) enables excitatory circuit long-term potentiation (LTP). Here, we investigated its involvement in the enhancement of inhibitory synapses. Activation of GABA neurons suppressed neuronal responses in the neocortex to a forthcoming auditory stimulus in mice of both sexes. High-frequency laser stimulation (HFLS) of GABAergic neurons potentiated this suppression. HFLS of CCK interneurons could induce the LTP of their inhibition toward pyramidal neurons. This potentiation was abolished in CCK knock-out mice but intact in mice with both CCK1R and 2R knockout of both sexes. Next, we combined bioinformatics analysis, multiple unbiased cell-based assays, and histology examinations to identify a novel CCK receptor, GPR173. We propose GPR173 as CCK3R, which mediates the relationship between cortical CCK interneuron signaling and inhibitory LTP in the mice of either sex. Thus, GPR173 might represent a promising therapeutic target for brain disorders related to excitation and inhibition imbalance in the cortex.SIGNIFICANCE STATEMENT CCK, the most abundant and widely distributed neuropeptide in the CNS, colocalizes with many neurotransmitters and modulators. GABA is one of the important inhibitory neurotransmitters, and much evidence shows that CCK may be involved in modulating GABA signaling in many brain areas. However, the role of CCK-GABA neurons in the cortical microcircuits is still unclear. We identified a novel CCK receptor, GPR173, localized in the CCK-GABA synapses and mediated the enhancement of the GABA inhibition effect, which might represent a promising therapeutic target for brain disorders related to excitation and inhibition imbalance in the cortex.


Assuntos
GABAérgicos , Receptores da Colecistocinina , Masculino , Feminino , Camundongos , Animais , GABAérgicos/farmacologia , Células Piramidais/fisiologia , Sinapses/fisiologia , Neurônios GABAérgicos/fisiologia , Camundongos Knockout , Interneurônios , Colecistocinina , Ácido gama-Aminobutírico/fisiologia , Potenciação de Longa Duração/fisiologia , Receptores Acoplados a Proteínas G/genética
3.
Neuropsychopharmacology ; 47(10): 1816-1825, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35788684

RESUMO

Methamphetamine (METH) abuse is associated with the emergence of cognitive deficits and hypofrontality, a pathophysiological marker of many neuropsychiatric disorders that is produced by altered balance of local excitatory and inhibitory synaptic transmission. However, there is a dearth of information regarding the cellular and synaptic mechanisms underlying METH-induced cognitive deficits and associated hypofrontal states. Using PV-Cre transgenic rats that went through a METH sensitization regime or saline (SAL) followed by 7-10 days of home cage abstinence combined with cognitive tests, chemogenetic experiments, and whole-cell patch recordings on the prelimbic prefrontal cortex (PFC), we investigated the cellular and synaptic mechanisms underlying METH-induce hypofrontality. We report here that repeated METH administration in rats produces deficits in working memory and increases in inhibitory synaptic transmission onto pyramidal neurons in the PFC. The increased PFC inhibition is detected by an increase in spontaneous and evoked inhibitory postsynaptic synaptic currents (IPSCs), an increase in GABAergic presynaptic function, and a shift in the excitatory-inhibitory balance onto PFC deep-layer pyramidal neurons. We find that pharmacological blockade of D1 dopamine receptor function reduces the METH-induced augmentation of IPSCs, suggesting a critical role for D1 dopamine signaling in METH-induced hypofrontality. In addition, repeated METH administration increases the intrinsic excitability of parvalbumin-positive fast spiking interneurons (PV + FSIs), a key local interneuron population in PFC that contributes to the control of inhibitory tone. Using a cell type-specific chemogenetic approach, we show that increasing PV + FSIs activity in the PFC is necessary and sufficient to cause deficits in temporal order memory similar to those induced by METH. Conversely, reducing PV + FSIs activity in the PFC of METH-exposed rats rescues METH-induced temporal order memory deficits. Together, our findings reveal that repeated METH exposure increases PFC inhibitory tone through a D1 dopamine signaling-dependent potentiation of inhibitory synaptic transmission, and that reduction of PV + FSIs activity can rescue METH-induced cognitive deficits, suggesting a potential therapeutic approach to treating cognitive symptoms in patients suffering from METH use disorder.


Assuntos
Transtornos Cognitivos , Cognição , GABAérgicos , Metanfetamina , Córtex Pré-Frontal , Transmissão Sináptica , Animais , Cognição/efeitos dos fármacos , Transtornos Cognitivos/induzido quimicamente , Dopamina/farmacologia , GABAérgicos/toxicidade , Interneurônios/fisiologia , Metanfetamina/toxicidade , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Células Piramidais , Ratos , Receptores de Dopamina D1 , Transmissão Sináptica/efeitos dos fármacos
4.
Exp Physiol ; 107(3): 233-242, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35137999

RESUMO

NEW FINDINGS: What is the central question of this study? Is there an interaction between histamine and the GABAergic system in modulation of anxiety in mice? What is the main finding and its importance? There is a synergistic anxiogenic effect between histamine and bicuculline in mice. This effect may be due to a direct or an indirect effect of the histaminergic system on the GABAergic system. ABSTRACT: It has been documented that both histaminergic and GABAergic systems participate in the neurobiology of anxiety behaviour. In the current research, we investigated the effects of the histaminergic system and GABAA receptor agents on anxiety-related behaviours and their interaction using the elevated plus maze test in mice. Intraperitoneal (i.p.) administration of muscimol (0.12 and 0.25 mg/kg) increased the open arm time (OAT) (P < 0.001) without affecting the open arm entries (OAE) and locomotor activity, showing an anxiolytic effect. i.p. injection of bicuculline (0.5 and 1 mg/kg) decreased OAT (P < 0.001) but not OAE and locomotor activity, suggesting an anxiogenic behaviour. Intracerebroventricular (i.c.v.) microinjection of histamine (2.5 and 5 µg/mouse) resulted in a decline in OAT (P < 0.001) but not OAE and locomotor activity, indicating an anxiogenic response. Co-administration of histamine with GABAergic agents, muscimol (0.06 mg/kg; i.p.) and bicuculline (0.25 mg/kg; i.p.), decreased (P < 0.001) and increased (P < 0.05), respectively, the anxiogenic-like response to the effective dose (5 µg/mouse; i.c.v.) of histamine. In addition, co-treatment of effective doses of histamine (2.5 and 5 µg/mouse;i.c.v.) with an effective dose of muscimol (0.12 mg/kg; i.p.) and a non-effective dose of bicuculline (0.25 mg/kg; i.p.) significantly decreased OAT (P < 0.001), suggesting a likely interaction between the histaminergic and GABAergic systems in the regulation of anxiety. The results demonstrated a synergistic anxiogenic-like effect between histamine and bicuculline in mice. In conclusion, our results present an interaction between the histaminergic and GABAergic systems in anxiolytic/anxiogenic-like behaviours in the elevated plus maze test.


Assuntos
Teste de Labirinto em Cruz Elevado , Histamina , Animais , Ansiedade/tratamento farmacológico , GABAérgicos/farmacologia , Histamina/farmacologia , Masculino , Aprendizagem em Labirinto , Camundongos , Ratos , Ratos Wistar , Ácido gama-Aminobutírico/farmacologia , Ácido gama-Aminobutírico/fisiologia
5.
Pediatr Neurol ; 128: 52-57, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35093793

RESUMO

BACKGROUND: Chronic headache disorders can cause substantial disability and be treatment refractory. Often, these patients are excluded from clinical trials with leaving little evidence to guide treatment. In adults, divalproex sodium is an effective preventive migraine treatment. METHODS: All pediatric patients admitted for first-time sodium valproate infusions to treat refractory, chronic migraine (CM), new daily persistent headache, or persistent headache attributed to head trauma from January 2017 to October 2020 were identified for review. Each patient underwent a standardized, 4-day protocol. A new preventive was started one week after discharge. Data on headache frequency, severity, and acute medication use were collected through preadmission and postadmission clinic notes. Safety and tolerability were evaluated. Results were evaluated using descriptive statistics and compared with paired t-tests. RESULTS: Forty-five patients were identified for review. Patients with CM had a median of 7 previous preventive trials, and 85% had previously received alternative intravenous treatment for headache. Baseline headache pain significant decreased from 6.9/10 to 5.4/10 by 7-week postadmission follow up, (95% confidence interval = -0.7 to -2.4), P < 0.001. Use of medications for acute headache treatment decreased significantly from 2.1 days/week to 1.5 days/week, (95% confidence interval = -0.3 to -1), P < 0.001. Baseline headache frequency did not significantly change. At postadmission follow-up, 26 of 39 (67%) patients saw improvements in headache frequency, headache intensity, and/or acute pain medication usage. There were no serious adverse events. CONCLUSIONS: Repetitive sodium valproate infusions were well tolerated and significantly reduced baseline headache intensity and acute medication usage in pediatric patients with refractory, chronic headache disorders.


Assuntos
GABAérgicos/administração & dosagem , Transtornos da Cefaleia/tratamento farmacológico , Ácido Valproico/administração & dosagem , Adolescente , Fatores Etários , Criança , Pré-Escolar , Doença Crônica , Feminino , Hospitalização , Humanos , Infusões Intravenosas , Masculino , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento
6.
Pharmacol Biochem Behav ; 213: 173321, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35041859

RESUMO

GABAkines, or positive allosteric modulators of γ-aminobutyric acid-A (GABAA) receptors, are used for the treatment of anxiety, epilepsy, sleep, and other disorders. The search for improved GABAkines, with reduced safety liabilities (e.g., dependence) or side-effect profiles (e.g., sedation) constituted multiple discovery and development campaigns that involved a multitude of strategies over the past century. Due to the general lack of success in the development of new GABAkines, there had been a decades-long draught in bringing new GABAkines to market. Recently, however, there has been a resurgence of efforts to bring GABAkines to patients, the FDA approval of the neuroactive steroid brexanolone for post-partum depression in 2019 being the first. Other neuroactive steroids are in various stages of clinical development (ganaxolone, zuranolone, LYT-300, Sage-324, PRAX 114, and ETX-155). These GABAkines and non-steroid compounds (GRX-917, a TSPO binding site ligand), darigabat (CVL-865), an α2/3/5-preferring GABAkine, SAN711, an α3-preferring GABAkine, and the α2/3-preferring GABAkine, KRM-II-81, bring new therapeutic promise to this highly utilized medicinal target in neurology and psychiatry. Herein, we also discuss possible conditions that have enabled the transition to a new age of GABAkines. We highlight the pharmacology of KRM-II-81 that has the most preclinical data reported. KRM-II-81 is the lead compound in a new series of orally bioavailable imidazodiazepines entering IND-enabling safety studies. KRM-II-81 has a preclinical profile predicting efficacy against pharmacoresistant epilepsies, traumatic brain injury, and neuropathic pain. KRM-II-81 also produces anxiolytic- and antidepressant-like effects in rodent models. Other key features of the pharmacology of this compound are its low sedation rate, lack of tolerance development, and the ability to prevent the development of seizure sensitization.


Assuntos
GABAérgicos/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Doenças do Sistema Nervoso/tratamento farmacológico , Oxazóis/uso terapêutico , Receptores de GABA/metabolismo , Animais , Ansiolíticos/uso terapêutico , Anticonvulsivantes/uso terapêutico , Antidepressivos/uso terapêutico , Ansiedade/tratamento farmacológico , Epilepsia/tratamento farmacológico , GABAérgicos/farmacologia , Agonistas de Receptores de GABA-A/uso terapêutico , Humanos , Neuralgia/tratamento farmacológico , Oxazóis/farmacologia , Receptores de GABA-A/metabolismo , Convulsões/tratamento farmacológico
7.
Int J Mol Sci ; 22(23)2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34884481

RESUMO

Drought seriously affects the yield and quality of apples. γ-aminobutyric acid (GABA) plays an important role in the responses of plants to various stresses. However, the role and possible mechanism of GABA in the drought response of apple seedlings remain unknown. To explore the effect of GABA on apple seedlings under drought stress, seedlings of Malus hupehensis were treated with seven concentrations of GABA, and the response of seedlings under 15-day drought stress was observed. The results showed that 0.5 mM GABA was the most effective at relieving drought stress. Treatment with GABA reduced the relative electrical conductivity and MDA content of leaves induced by drought stress and significantly increased the relative water content of leaves. Exogenous GABA significantly decreased the stomatal conductance and intercellular carbon dioxide concentration and transpiration rate, and it significantly increased the photosynthetic rate under drought. GABA also reduced the accumulation of superoxide anions and hydrogen peroxide in leaf tissues under drought and increased the activities of POD, SOD, and CAT and the content of GABA. Exogenous treatment with GABA acted through the accumulation of abscisic acid (ABA) in the leaves to significantly decrease stomatal conductance and increase the stomatal closure rate, and the levels of expression of ABA-related genes PYL4, ABI1, ABI2, HAB1, ABF3, and OST1 changed in response to drought. Taken together, exogenous GABA can enhance the drought tolerance of apple seedlings.


Assuntos
Ácido Abscísico/farmacologia , Secas , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Malus/crescimento & desenvolvimento , Proteínas de Plantas/metabolismo , Plântula/crescimento & desenvolvimento , Ácido gama-Aminobutírico/farmacologia , GABAérgicos/farmacologia , Malus/efeitos dos fármacos , Malus/genética , Malus/metabolismo , Reguladores de Crescimento de Plantas/farmacologia , Proteínas de Plantas/genética , Plântula/efeitos dos fármacos , Plântula/genética , Plântula/metabolismo , Estresse Fisiológico
8.
Cells ; 10(12)2021 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-34943913

RESUMO

Dendritic spines are small, thin, hair-like protrusions found on the dendritic processes of neurons. They serve as independent compartments providing large amplitudes of Ca2+ signals to achieve synaptic plasticity, provide sites for newer synapses, facilitate learning and memory. One of the common and severe complication of neurodegenerative disease is cognitive impairment, which is said to be closely associated with spine pathologies viz., decreased in spine density, spine length, spine volume, spine size etc. Many treatments targeting neurological diseases have shown to improve the spine structure and distribution. However, concise data on the various modulators of dendritic spines are imperative and a need of the hour. Hence, in this review we made an attempt to consolidate the effects of various pharmacological (cholinergic, glutamatergic, GABAergic, serotonergic, adrenergic, and dopaminergic agents) and non-pharmacological modulators (dietary interventions, enriched environment, yoga and meditation) on dendritic spines structure and functions. These data suggest that both the pharmacological and non-pharmacological modulators produced significant improvement in dendritic spine structure and functions and in turn reversing the pathologies underlying neurodegeneration. Intriguingly, the non-pharmacological approaches have shown to improve intellectual performances both in preclinical and clinical platforms, but still more technology-based evidence needs to be studied. Thus, we conclude that a combination of pharmacological and non-pharmacological intervention may restore cognitive performance synergistically via improving dendritic spine number and functions in various neurological disorders.


Assuntos
Espinhas Dendríticas/efeitos dos fármacos , Dieta , Doenças Neurodegenerativas/dietoterapia , Doenças Neurodegenerativas/tratamento farmacológico , Colinérgicos/uso terapêutico , Disfunção Cognitiva/dietoterapia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/psicologia , Espinhas Dendríticas/patologia , Espinhas Dendríticas/fisiologia , Fármacos Atuantes sobre Aminoácidos Excitatórios/uso terapêutico , GABAérgicos/uso terapêutico , Humanos , Meditação/psicologia , Doenças Neurodegenerativas/epidemiologia , Doenças Neurodegenerativas/psicologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Yoga/psicologia
9.
Elife ; 102021 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-34855580

RESUMO

The repressor-element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF) controls hundreds of neuron-specific genes. We showed that REST/NRSF downregulates glutamatergic transmission in response to hyperactivity, thus contributing to neuronal homeostasis. However, whether GABAergic transmission is also implicated in the homeostatic action of REST/NRSF is unknown. Here, we show that hyperactivity-induced REST/NRSF activation, triggers a homeostatic rearrangement of GABAergic inhibition, with increased frequency of miniature inhibitory postsynaptic currents (IPSCs) and amplitude of evoked IPSCs in mouse cultured hippocampal neurons. Notably, this effect is limited to inhibitory-onto-excitatory neuron synapses, whose density increases at somatic level and decreases in dendritic regions, demonstrating a complex target- and area-selectivity. The upscaling of perisomatic inhibition was occluded by TrkB receptor inhibition and resulted from a coordinated and sequential activation of the Npas4 and Bdnf gene programs. On the opposite, the downscaling of dendritic inhibition was REST-dependent, but BDNF-independent. The findings highlight the central role of REST/NRSF in the complex transcriptional responses aimed at rescuing physiological levels of network activity in front of the ever-changing environment.


Assuntos
Potenciais Pós-Sinápticos Inibidores/fisiologia , Neurônios/metabolismo , Proteínas Repressoras/metabolismo , Animais , Células Cultivadas , GABAérgicos , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hipocampo/citologia , Homeostase , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Receptor trkB/metabolismo , Sinapses/metabolismo , Fatores de Transcrição
10.
Sci Rep ; 11(1): 19407, 2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-34593892

RESUMO

Animal behaviour is closely related to individual fitness, which allows animals to choose suitable mates or avoid predation. The central nervous system regulates many aspects of animal behaviour responses. Therefore, behavioural responses can be especially sensitive to compounds with a neurodevelopmental or neurofunctional mode of action. Phototactic behavioural changes against fish in the freshwater crustacean Daphnia magna have been the subject of many ecological investigations. The aim of this study was to identify which neurotransmitter systems modulate phototactic behaviour to fish kairomones. We used a positive phototactic D. magna clone (P132,85) that shows marked negative phototactism after exposure to fish kairomones. Treatments included up to 16 known agonists and antagonists of the serotonergic, cholinergic, dopaminergic, histaminergic, glutamatergic and GABAergic systems. It was hypothesized that many neurological signalling pathways may modulate D. magna phototactic behaviour to fish kairomones. A new custom-designed device with vertically oriented chambers was used, and changes in the preferred areas (bottom, middle, and upper areas) were analysed using groups of animals after 24 h of exposure to the selected substance(s). The results indicated that agonists of the muscarinic acetylcholine and GABAA receptors and their equi-effective mixture ameliorated the negative phototactic response to fish kairomones, whereas antagonists and their mixtures increased the negative phototactism to fish kairomones. Interestingly, inhibition of the muscarinic acetylcholine receptor abolished positive phototaxis, thus inducing the phototactic response to fish kairomones. Analysis of the profile of neurotransmitters and their related metabolites showed that the D. magna behavioural responses induced by fish depend on changes in the levels of acetylcholine, dopamine and GABA.


Assuntos
Comportamento Animal/efeitos dos fármacos , Quimiotaxia/efeitos dos fármacos , Colinérgicos/farmacologia , Daphnia/metabolismo , Feromônios/metabolismo , Fototaxia/efeitos dos fármacos , Animais , GABAérgicos/farmacologia
11.
Biomed Pharmacother ; 142: 112021, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34463268

RESUMO

Valproic acid (VPA) is an approved drug for managing epileptic seizures, bipolar disorders, and migraine. VPA has been shown to elevate the level of gamma-aminobutyric acid (GABA) in the brain through competitive inhibition of GABA transaminase, thus promoting the availability of synaptic GABA and facilitating GABA-mediated responses. VPA, which is a small chain of fatty acids, prevents histone deacetylases (HDACs). HDACs play a crucial role in chromatin remodeling and gene expression through posttranslational changes of chromatin-associated histones. Recent studies reported a possible effect of VPA against particular types of cancers. This effect was partially attributed to its role in regulating epigenetic modifications through the inhibition of HDACs, which affect the expression of genes associated with cell cycle control, cellular differentiation, and apoptosis. In this review, we summarize the current information on the actions of VPA in diseases such as diabetes mellitus, kidney disorders, neurodegenerative diseases, muscular dystrophy, and cardiovascular disorders.


Assuntos
GABAérgicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Ácido Valproico/farmacologia , Animais , Anticonvulsivantes/farmacologia , Apoptose/efeitos dos fármacos , Epigênese Genética , Histona Desacetilases/efeitos dos fármacos , Histona Desacetilases/metabolismo , Humanos
12.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360626

RESUMO

Neurodevelopmental exposure to psychoactive compounds in cannabis, specifically THC, is associated with a variety of long-term psychopathological outcomes. This increased risk includes a higher prevalence of schizophrenia, mood and anxiety disorders, and cognitive impairments. Clinical and pre-clinical research continues to identify a wide array of underlying neuropathophysiological sequelae and mechanisms that may underlie THC-related psychiatric risk vulnerability, particularly following adolescent cannabis exposure. A common theme among these studies is the ability of developmental THC exposure to induce long-term adaptations in the mesocorticolimbic system which resemble pathological endophenotypes associated with these disorders. This narrative review will summarize recent clinical and pre-clinical evidence that has elucidated these THC-induced developmental risk factors and examine how specific pharmacotherapeutic interventions may serve to reverse or perhaps prevent these cannabis-related risk outcomes.


Assuntos
Cannabis/efeitos adversos , Dronabinol/efeitos adversos , GABAérgicos/uso terapêutico , Transtornos do Neurodesenvolvimento/induzido quimicamente , Psicologia do Adolescente , Animais , Humanos , Transtornos do Neurodesenvolvimento/tratamento farmacológico
13.
Elife ; 102021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34251335

RESUMO

Subplate neurons (SPNs) are thought to play a role in nascent sensory processing in neocortex. To better understand how heterogeneity within this population relates to emergent function, we investigated the synaptic connectivity of Lpar1-EGFP SPNs through the first postnatal week in whisker somatosensory cortex (S1BF). These SPNs comprise of two morphological subtypes: fusiform SPNs with local axons and pyramidal SPNs with axons that extend through the marginal zone. The former receive translaminar synaptic input up until the emergence of the whisker barrels, a timepoint coincident with significant cell death. In contrast, pyramidal SPNs receive local input from the subplate at early ages but then - during the later time window - acquire input from overlying cortex. Combined electrical and optogenetic activation of thalamic afferents identified that Lpar1-EGFP SPNs receive sparse thalamic innervation. These data reveal components of the postnatal network that interpret sparse thalamic input to direct the emergent columnar structure of S1BF.


Assuntos
Proteínas de Fluorescência Verde/metabolismo , Neurônios/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Córtex Somatossensorial/metabolismo , Animais , Animais Recém-Nascidos , Axônios/metabolismo , Estimulação Elétrica/métodos , GABAérgicos/metabolismo , Camundongos , Optogenética/métodos , Tálamo/metabolismo , Vibrissas/metabolismo
14.
Neuropharmacology ; 197: 108724, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34284042

RESUMO

α5 subunit GABA type A receptor (GABAAR) preferring negative allosteric modulators (NAMs) are cognitive enhancers with antidepressant-like effects. α5-NAM success in treating mouse models of neurodevelopmental disorders with excessive inhibition have led to Phase 2 clinical trials for Down syndrome. Despite in vivo efficacy, no study has examined the effects of continued α5-NAM treatment on inhibitory and excitatory synapse plasticity to identify mechanisms of action. Here we used L-655,708, an imidazobenzodiazepine that acts as a highly selective but weak α5-NAM, to investigate the impact of sustained treatment on hippocampal neuron synapse and dendrite development. We show that 2-day pharmacological reduction of α5-GABAAR signaling from DIV12-14, when GABAARs contribute to depolarization, delays dendritic spine maturation and the NMDA receptor (NMDAR) GluN2B/GluN2A developmental shift. In contrast, α5-NAM treatment from DIV19-21, when hyperpolarizing GABAAR signaling predominates, enhances surface synaptic GluN2A while decreasing GluN2B. Despite changes in NMDAR subtype surface levels and localization, total levels of key excitatory synapse proteins were largely unchanged, and mEPSCs were unaltered. Importantly, 2-day α5-NAM treatment does not alter the total surface levels or distribution of α5-GABAARs, reduce the gephyrin inhibitory synaptic scaffold, or impair phasic or tonic inhibition. Furthermore, α5-NAM inhibition of the GABAAR tonic current in mature neurons is maintained after 2-day α5-NAM treatment, suggesting reduced tolerance liability, in contrast to other clinically relevant GABAAR-targeting drugs such as benzodiazepines. Together, these results show that α5-GABAARs contribute to dendritic spine maturation and excitatory synapse development via a NMDAR dependent mechanism without perturbing overall neuronal excitability.


Assuntos
GABAérgicos/farmacologia , Imidazóis/farmacologia , Receptores de GABA-A/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Ácido gama-Aminobutírico/fisiologia , Animais , Dendritos/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Antagonistas de Receptores de GABA-A/farmacologia , Ratos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Sinapses/efeitos dos fármacos
15.
J Psychopharmacol ; 35(12): 1496-1509, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34278874

RESUMO

BACKGROUND: Inhibitory control is a crucial executive function with high relevance to mental and physical well-being. However, there are still unanswered questions regarding its neural mechanisms, including the role of the major inhibitory neurotransmitter, γ-aminobutyric acid (GABA). AIMS: This study examined the effects of lorazepam (0.5 mg and 1 mg), a positive allosteric modulator at the GABAA receptor, on response inhibition and interference control. We also explored the heterogeneity of inhibitory control and calculated delta plots to explore whether lorazepam affects the gradual build-up of inhibition and activation over time. METHODS: N = 50 healthy participants performed antisaccade, Eriksen flanker and Simon tasks in a within-subjects, placebo-controlled, double-blind randomized design. RESULTS: Lorazepam increased reaction time (RT) and error rates dose dependently in all tasks (p ⩽ 0.005). In the antisaccade and Simon tasks, lorazepam increased congruency effects for error rate (p ⩽ 0.029) but not RT (p ⩾ 0.587). In the Eriksen flanker task, both congruency effects were increased by the drug (p ⩽ 0.031). Delta plots did not reflect drug-induced changes in inhibition and activation over time. Delta plots for RT in the Simon task were negative-going, as expected, whereas those for the antisaccade and flanker tasks were positive-going. CONCLUSIONS: This study provides evidence for GABAergic involvement in performance on response inhibition and interference control tasks. Furthermore, our findings highlight the diversity of the broader construct of inhibitory control while also pointing out similarities between different inhibitory control tasks. In contrast to RT and error rates, the cognitive processes indexed by delta plots may not be sensitive to GABAergic modulation.


Assuntos
Atenção/efeitos dos fármacos , Função Executiva/efeitos dos fármacos , GABAérgicos/farmacologia , Inibição Psicológica , Lorazepam/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Receptores de GABA-A/efeitos dos fármacos , Adulto Jovem
16.
Front Immunol ; 12: 667136, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34149704

RESUMO

The neurotransmitter γ-aminobutyric acid (GABA) is known to affect the activation and function of immune cells. This study investigated the role of GABA transporter (GAT)-2 in the differentiation of type 1 helper T (Th1) cells. Naïve CD4+ T cells isolated from splenocytes of GAT-2 knockout (KO) and wild-type (WT) mice were cultured; Th1 cell differentiation was induced and transcriptome and bioinformatics analyses were carried out. We found that GAT-2 deficiency promoted the differentiation of naïve T cells into Th1 cells. RNA sequencing revealed 2984 differentially expressed genes including 1616 that were up-regulated and 1368 that were down-regulated in GAT-2 KO cells compared to WT cells, which were associated with 950 enriched Gene Ontology terms and 33 enriched Kyoto Encyclopedia of Genes and Genomes pathways. Notably, 4 signal transduction pathways (hypoxia-inducible factor [HIF]-1, Hippo, phospholipase D, and Janus kinase [JAK]/signal transducer and activator of transcription [STAT]) and one metabolic pathway (glycolysis/gluconeogenesis) were significantly enriched by GAT-2 deficiency, suggesting that these pathways mediate the effect of GABA on T cell differentiation. Our results provide evidence for the immunomodulatory function of GABA signaling in T cell-mediated immunity and can guide future studies on the etiology and management of autoimmune diseases.


Assuntos
GABAérgicos/imunologia , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Transdução de Sinais/imunologia , Células Th1/imunologia , Ácido gama-Aminobutírico/metabolismo , Animais , Diferenciação Celular , Células Cultivadas , Proteínas da Membrana Plasmática de Transporte de GABA/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transcriptoma
17.
Exp Neurol ; 343: 113760, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34000248

RESUMO

General anesthetic agents are thought to induce loss-of-consciousness (LOC) and enable pain-free surgery by acting on the endogenous brain circuitry responsible for sleep-wake cycling. In clinical use, the entire CNS is exposed to anesthetic molecules with LOC and amnesia usually attributed to synaptic suppression in the cerebral cortex and immobility and analgesia to agent action in the spinal cord and brainstem. This model of patch-wise suppression has been challenged, however, by the observation that all functional components of anesthesia can be induced by focal delivery of minute quantities of GABAergic agonists to the brainstem mesopontine tegmental anesthesia area (MPTA). We compared spectral features of the cortical electroencephalogram (EEG) in rats during systemic anesthesia and anesthesia induced by MPTA microinjection. Systemic administration of (GABAergic) pentobarbital yielded the sustained, δ-band dominant EEG signature familiar in clinical anesthesia. In contrast, anesthesia induced by MPTA microinjection (pentobarbital or muscimol) featured epochs of δ-band EEG alternating with the wake-like EEG, the pattern typical of natural non-rapid-eye-movement (NREM) and REM sleep. The rats were not sleeping, however, as they remained immobile, atonic and unresponsive to noxious pinch. Recalling the paradoxical wake-like quality the EEG during REM sleep, we refer to this state as "paradoxical anesthesia". GABAergic anesthetics appear to co-opt both cortical and spinal components of the sleep network via dedicated axonal pathways driven by MPTA neurons. Direct drug exposure of cortical and spinal neurons is not necessary, and is probably responsible for off-target side-effects of systemic administration including monotonous δ-band EEG, hypothermia and respiratory depression. SIGNIFICANCE STATEMENT: The concept that GABAergic general anesthetic agents induce loss-of-consciousness by substituting for an endogenous neurotransmitter, thereby co-opting neural circuitry responsible for sleep-wake transitions, has gained considerable traction. However, the electroencephalographic (EEG) signatures of sleep and anesthesia differ fundamentally. We show that when the anesthetic state is generated by focal delivery of GABAergics into the mesopontine tegmental anesthesia area (MPTA) the resulting EEG repeatedly transitions between delta-wave-dominant and wake-like patterns much as in REM-NREM sleep. This suggests that systemic (clinical) anesthetic delivery, which indiscriminately floods the entire cerebrum with powerful inhibitory agents, obscures the sleep-like EEG signature associated with the less adulterated form of anesthesia obtained when the drugs are applied selectively to loci where the effective neurotransmitter substitution actually occurs.


Assuntos
Anestesia/métodos , Tronco Encefálico/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , GABAérgicos/administração & dosagem , Microinjeções/métodos , Fases do Sono/efeitos dos fármacos , Animais , Tronco Encefálico/fisiologia , Eletroencefalografia/métodos , Feminino , Masculino , Ratos , Ratos Wistar , Reflexo de Endireitamento/efeitos dos fármacos , Reflexo de Endireitamento/fisiologia , Fases do Sono/fisiologia
18.
Traffic Inj Prev ; 22(5): 366-371, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33960857

RESUMO

OBJECTIVE: Sleep deprivation is known to affect driving behavior and may lead to serious car accidents similar to the effects from e.g., alcohol. In a previous study, we have demonstrated that the use of machine learning techniques allows adequate characterization of abnormal driving behavior after alprazolam and/or alcohol intake. In the present study, we extend this approach to sleep deprivation and test the model for characterization of new interventions. We aimed to classify abnormal driving behavior after sleep deprivation, and, by using a machine learning model, we tested if this model could also pick up abnormal driving behavior resulting from other interventions. METHODS: Data were collected during a previous study, in which 24 subjects were tested after being sleep-deprived and after a well-rested night. Features were calculated from several driving parameters, such as the lateral position, speed of the car, and steering speed. In the present study, we used a gradient boosting model to classify sleep deprivation. The model was validated using a 5-fold cross validation technique. Next, probability scores were used to identify the overlap of driving behavior after sleep deprivation and driving behavior affected by other interventions. In the current study alprazolam, alcohol, and placebo are used to test/validate the approach. RESULTS: The sleep deprivation model detected abnormal driving behavior in the simulator with an accuracy of 77 ± 9%. Abnormal driving behavior after alprazolam, and to a lesser extent also after alcohol intake, showed remarkably similar characteristics to sleep deprivation. The average probability score for alprazolam and alcohol measurements was 0.79, for alcohol 0.63, and for placebo only 0.27 and 0.30, matching the expected relative drowsiness. CONCLUSION: We developed a model detecting abnormal driving induced by sleep deprivation. The model shows the similarities in driving characteristics between sleep deprivation and other interventions, i.e., alcohol and alprazolam. Consequently, our model for sleep deprivation may serve as a next reference point for a driving test battery of newly developed drugs.


Assuntos
Acidentes de Trânsito/prevenção & controle , Atenção/fisiologia , Tempo de Reação/fisiologia , Privação do Sono/fisiopatologia , Adulto , Alprazolam/uso terapêutico , Condução de Veículo , Simulação por Computador/estatística & dados numéricos , GABAérgicos/uso terapêutico , Humanos , Aprendizado de Máquina , Masculino , Vigília/fisiologia
19.
Proc Natl Acad Sci U S A ; 118(19)2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33952696

RESUMO

Transcriptional dysregulation in Huntington's disease (HD) causes functional deficits in striatal neurons. Here, we performed Patch-sequencing (Patch-seq) in an in vitro HD model to investigate the effects of mutant Huntingtin (Htt) on synaptic transmission and gene transcription in single striatal neurons. We found that expression of mutant Htt decreased the synaptic output of striatal neurons in a cell autonomous fashion and identified a number of genes whose dysregulation was correlated with physiological deficiencies in mutant Htt neurons. In support of a pivotal role for epigenetic mechanisms in HD pathophysiology, we found that inhibiting histone deacetylase 1/3 activities rectified several functional and morphological deficits and alleviated the aberrant transcriptional profiles in mutant Htt neurons. With this study, we demonstrate that Patch-seq technology can be applied both to better understand molecular mechanisms underlying a complex neurological disease at the single-cell level and to provide a platform for screening for therapeutics for the disease.


Assuntos
GABAérgicos/farmacologia , Doença de Huntington/genética , Neurônios/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Animais , Benzamidas , Corpo Estriado/fisiologia , Modelos Animais de Doenças , Expressão Gênica , Proteína Huntingtina , Doença de Huntington/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência de RNA , Transmissão Sináptica/genética , Transcriptoma
20.
Neurobiol Learn Mem ; 183: 107462, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34015444

RESUMO

Autism spectrum disorder (ASD) is a severe life-long neuropsychiatric disorder. Alterations and imbalance of several neurochemical systems may be involved in ASD pathophysiology, of them, serotonergic neurotransmission dysfunction and deficiency may underlie behavioral abnormalities associated with ASD. However, the functional importance of serotonergic receptors, particularly 5HT7 receptors in ASD pathology remains poorly defined. Serotonin receptor subtype 7 (5-HT7R) plays a direct regulatory role in the development and also for the mature function of the brain, therefore, further studies are necessary to elucidate the role of these receptors in the etiology of autism. To address this issue, we combined here behavioral, electrophysiological methods to further characterize the contribution of 5-HT7Rs in the prenatal valproic acid (VPA) exposure-induced impairment in synaptic plasticity and their impact on the associated behavioral changes. This may help to unravel the underlying cellular mechanisms involved in ASD and can lead to new treatment and/or prevention therapies based on the role of the serotonergic system for autism. Findings revealed that compared to control, autistic-like offspring showed increased anxiety-like behavior, reduced social interaction, decreased locomotor activity, and impaired identification of the novel object. However, administration of 5-HT7Rs agonist, LP-211, for 7 consecutive days before testing from postnatal day 21 to 27 reversed all behavioral deficits induced by prenatal exposure to VPA in offspring. Also, both short-term depression and long-term potentiation were impaired in the autistic-like pups, but activation of 5-HT7Rs rescued the LTP impairment in the autistic-like group so that there was no significant difference between the two groups. Blockade of 5-HT7Rs caused LTP impairment following HFS in the autistic-like group. Besides, there was a significant difference in LTD induction following SB-269970 application between the control and the autistic-like groups measured at first 10 min following TPS. Moreover, both the number and the size of retrograde fast blue-labelled neurons in the raphe nuclei were reduced. Overall, these results provide for the first time, as far as we know, functional evidence for the restorative role of 5-HT7Rs activation against prenatal VPA exposure induced behavioral deficits and hippocampal synaptic plasticity impairment. Therefore, these receptors could be a potential and promising pharmacotherapy target for the treatment of autism.


Assuntos
Transtorno do Espectro Autista/metabolismo , Região CA1 Hipocampal/metabolismo , Potenciação de Longa Duração/fisiologia , Receptores de Serotonina/metabolismo , Animais , Transtorno do Espectro Autista/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Região CA1 Hipocampal/fisiopatologia , Modelos Animais de Doenças , Teste de Labirinto em Cruz Elevado , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , GABAérgicos/toxicidade , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Potenciação de Longa Duração/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Teste de Campo Aberto , Fenóis/farmacologia , Piperazinas/farmacologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Núcleos da Rafe/metabolismo , Núcleos da Rafe/patologia , Ratos , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Comportamento Social , Sulfonamidas/farmacologia , Ácido Valproico/toxicidade
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