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1.
J Neurosci ; 40(12): 2485-2497, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-32051327

RESUMO

We recently developed a rat model of relapse to drug seeking after food choice-induced voluntary abstinence. Here, we used this model to study the role of the orbitofrontal cortex (OFC) and its afferent projections in relapse to fentanyl seeking. We trained male and female rats to self-administer palatable food pellets for 6 d (6 h/d) and intravenous fentanyl (2.5 µg/kg/infusion) for 12 d (6 h/d). We assessed relapse to fentanyl seeking after 13-14 voluntary abstinence days, achieved through a discrete choice procedure between fentanyl infusions and palatable food (20 trials/d). In both sexes, relapse after food choice-induced abstinence was associated with increased expression of the activity marker Fos in the OFC. Pharmacological inactivation of the OFC with muscimol plus baclofen (50 + 50 ng/side) decreased relapse to fentanyl seeking. We then determined projection-specific activation of OFC afferents during the relapse test by using Fos plus the retrograde tracer cholera toxin B (injected into the OFC). Relapse to fentanyl seeking was associated with increased Fos expression in the piriform cortex (Pir) neurons projecting to the OFC, but not in projections from the basolateral amygdala and thalamus. Pharmacological inactivation of the Pir with muscimol plus baclofen decreased relapse to fentanyl seeking after voluntary abstinence. Next, we used an anatomical disconnection procedure to determine whether projections between the Pir and OFC are critical for relapse to fentanyl seeking. Unilateral muscimol plus baclofen injections into the Pir in one hemisphere plus unilateral muscimol plus baclofen injections into the OFC in the contralateral, but not ipsilateral, hemisphere decreased relapse. Our results identify Pir-OFC projections as a new motivation-related pathway critical to relapse to opioid seeking after voluntary abstinence.SIGNIFICANCE STATEMENT There are few preclinical studies of fentanyl relapse, and these studies have used experimenter-imposed extinction or forced abstinence procedures. In humans, however, abstinence is often voluntary, with drug available in the drug environment but forgone in favor of nondrug alternative reinforcers. We recently developed a rat model of drug relapse after palatable food choice-induced voluntary abstinence. Here, we used classical pharmacology, immunohistochemistry, and retrograde tracing to demonstrate a critical role of the piriform and orbitofrontal cortices in relapse to opioid seeking after voluntary abstinence.


Assuntos
Analgésicos Opioides , Comportamento de Procura de Droga , Fentanila , Transtornos Relacionados ao Uso de Opioides/fisiopatologia , Transtornos Relacionados ao Uso de Opioides/psicologia , Córtex Piriforme/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Animais , Baclofeno/administração & dosagem , Baclofeno/farmacologia , Comportamento de Escolha , Feminino , Preferências Alimentares , Agonistas GABAérgicos/administração & dosagem , Agonistas GABAérgicos/farmacologia , Expressão Gênica/efeitos dos fármacos , Genes fos , Masculino , Microinjeções , Muscimol/administração & dosagem , Muscimol/farmacologia , Ratos , Ratos Sprague-Dawley , Recidiva , Autoadministração
2.
J Neurosci ; 40(9): 1849-1861, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-31949108

RESUMO

Severe loss of excitatory synapses in key brain regions is thought to be one of the major mechanisms underlying stress-induced cognitive impairment. To date, however, the identity of the affected circuits remains elusive. Here we examined the effect of exposure to repeated multiple concurrent stressors (RMS) on the connectivity of the posterior parietal cortex (PPC) in adolescent male mice. We found that RMS led to layer-specific elimination of excitatory synapses with the most pronounced loss observed in deeper cortical layers. Quantitative analysis of cortical projections to the PPC revealed a significant loss of sensory and retrosplenial inputs to the PPC while contralateral and frontal projections were preserved. These results were confirmed by decreased synaptic strength from sensory, but not from contralateral, projections in stress-exposed animals. Functionally, RMS disrupted visuospatial working memory performance, implicating disrupted higher-order visual processing. These effects were not observed in mice subjected to restraint-only stress for an identical period of time. The PPC is considered to be a cortical hub for multisensory integration, working memory, and perceptual decision-making. Our data suggest that sensory information streams targeting the PPC may be impacted by recurring stress, likely contributing to stress-induced cognitive impairment.SIGNIFICANCE STATEMENT Repeated exposure to stress profoundly impairs cognitive functions like memory, attention, or decision-making. There is emerging evidence that stress not only impacts high-order regions of the brain, but may affect earlier stages of cognitive processing. Our work focuses on the posterior parietal cortex, a brain region supporting short-term memory, multisensory integration, and decision-making. We show evidence that repeated stress specifically damages sensory inputs to this region. This disruption of synaptic connectivity is linked to working memory impairment and is specific to repeated exposure to multiple stressors. Altogether, our data provide a potential alternative explanation to ailments previously attributed to downstream, cognitive brain structures.


Assuntos
Rede Nervosa/fisiopatologia , Lobo Parietal/fisiopatologia , Estresse Psicológico/fisiopatologia , Animais , Cognição , Fenômenos Eletrofisiológicos , Lateralidade Funcional , Agonistas GABAérgicos/farmacologia , Imuno-Histoquímica , Masculino , Memória de Curto Prazo , Camundongos , Camundongos Endogâmicos C57BL , Muscimol/farmacologia , Rede Nervosa/efeitos dos fármacos , Ruído , Optogenética , Lobo Parietal/efeitos dos fármacos , Restrição Física , Memória Espacial , Estresse Psicológico/psicologia , Sinapses , Percepção Visual
3.
Biochem Biophys Res Commun ; 520(2): 449-452, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31607482

RESUMO

Hippocampus CA1 pyramidal cells receive γ-aminobutyric acid (GABA) release from multiple GABAergic interneurons. Combining optogenetic strategy and whole-cell recordings, we demonstrate that baclofen, a specific GABAB receptor agonist, depresses monosynaptic GABAA receptor-mediated transmission from parvalbumin (PV)-expressing interneuron terminals onto pyramidal cells with less efficacy than that from the unspecific GABAergic terminals. The depression from PV neuron terminals is mainly mediated by presynaptic P/N type calcium channels. The results suggest that GABAB receptors are widely expressed on GABAergic interneurons, where they exert inhibition onto pyramidal cells by GABA release with different efficacy. The data strengthen the proposal that diverse GABA neurons play different roles in modulating CA1 pyramidal cell excitability.


Assuntos
Neurônios GABAérgicos/metabolismo , Hipocampo/metabolismo , Receptores de GABA-B/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Baclofeno/farmacologia , Canais de Cálcio/metabolismo , Feminino , Agonistas GABAérgicos/farmacologia , Antagonistas de Receptores de GABA-B/farmacologia , Hipocampo/citologia , Interneurônios/metabolismo , Masculino , Camundongos Transgênicos , Optogenética , Parvalbuminas/metabolismo , Técnicas de Patch-Clamp , Células Piramidais/metabolismo
4.
Immunohorizons ; 3(10): 498-510, 2019 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-31636084

RESUMO

Immune cells express γ-aminobutyric acid receptors (GABA-R), and GABA administration can inhibit effector T cell responses in models of autoimmune disease. The pharmacokinetic properties of GABA, however, may be suboptimal for clinical applications. The amino acid homotaurine is a type A GABA-R (GABAA-R) agonist with good pharmacokinetics and appears safe for human consumption. In this study, we show that homotaurine inhibits in vitro T cell proliferation to a similar degree as GABA but at lower concentrations. In vivo, oral homotaurine treatment had a modest ability to reverse hyperglycemia in newly hyperglycemic NOD mice but was ineffective after the onset of severe hyperglycemia. In severely diabetic NOD mice, the combination of homotaurine and low-dose anti-CD3 treatment significantly increased 1) disease remission, 2) the percentages of splenic CD4+and CD8+ regulatory T cells compared with anti-CD3 alone, and 3) the frequencies of CD4+ and CD8+ regulatory T cells in the pancreatic lymph nodes compared with homotaurine monotherapy. Histological examination of their pancreata provided no evidence of the large-scale GABAA-R agonist-mediated replenishment of islet ß-cells that has been reported by others. However, we did observe a few functional islets in mice that received combined therapy. Thus, GABAA-R activation enhanced CD4+and CD8+ regulatory T cell responses following the depletion of effector T cells, which was associated with the preservation of some functional islets. Finally, we observed that homotaurine treatment enhanced ß-cell replication and survival in a human islet xenograft model. Hence, GABAA-R agonists, such as homotaurine, are attractive candidates for testing in combination with other therapeutic agents in type 1 diabetes clinical trials.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Agonistas GABAérgicos/farmacologia , Agonistas GABAérgicos/uso terapêutico , Muromonab-CD3/uso terapêutico , Taurina/análogos & derivados , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/imunologia , Sinergismo Farmacológico , Feminino , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Transplante das Ilhotas Pancreáticas , Camundongos Endogâmicos NOD , Camundongos SCID , Muromonab-CD3/farmacologia , Taurina/farmacologia , Taurina/uso terapêutico
5.
eNeuro ; 6(5)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31519696

RESUMO

Rodent dorsal medial prefrontal cortex (mPFC), typically prelimbic cortex, is often described as promoting actions such as reward seeking, whereas ventral mPFC, typically infralimbic cortex, is thought to promote response inhibition. However, both dorsal and ventral mPFC are necessary for both expression and suppression of different behaviors, and each region may contribute to different functions depending on the specifics of the behavior tested. To better understand the roles of dorsal and ventral mPFC in motivated behavior we pharmacologically inactivated each area during operant fixed ratio 1 (FR1) seeking for a natural reward (sucrose), extinction, cue-induced reinstatement, and progressive ratio (PR) sucrose seeking in male Long-Evans rats. Bilateral inactivation of dorsal mPFC, but not ventral mPFC increased reward seeking during FR1. Inactivation of both dorsal and ventral mPFC decreased seeking during extinction. Bilateral inactivation of ventral mPFC, but not dorsal mPFC decreased reward seeking during cue-induced reinstatement. No effect of inactivation was found during PR. Our data contrast sharply with observations seen during drug seeking and fear conditioning, indicating that previously established roles of dorsal mPFC = going versus ventral mPFC = stopping are not applicable to all motivated behaviors and/or outcomes. Our results indicate that dichotomous functions of dorsal versus ventral mPFC, if they exist, may align better with other models, or may require the development of a new framework in which these multifaceted brain areas play different roles in action control depending on the behavioral context in which they are engaged.


Assuntos
Comportamento Aditivo/psicologia , Sinais (Psicologia) , Extinção Psicológica/fisiologia , Córtex Pré-Frontal/fisiologia , Recompensa , Sacarose/administração & dosagem , Animais , Comportamento Aditivo/induzido quimicamente , Extinção Psicológica/efeitos dos fármacos , Agonistas GABAérgicos/farmacologia , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Ratos Long-Evans , Autoadministração
6.
Cell ; 178(4): 867-886.e24, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398341

RESUMO

Somatosensory over-reactivity is common among patients with autism spectrum disorders (ASDs) and is hypothesized to contribute to core ASD behaviors. However, effective treatments for sensory over-reactivity and ASDs are lacking. We found distinct somatosensory neuron pathophysiological mechanisms underlie tactile abnormalities in different ASD mouse models and contribute to some ASD-related behaviors. Developmental loss of ASD-associated genes Shank3 or Mecp2 in peripheral mechanosensory neurons leads to region-specific brain abnormalities, revealing links between developmental somatosensory over-reactivity and the genesis of aberrant behaviors. Moreover, acute treatment with a peripherally restricted GABAA receptor agonist that acts directly on mechanosensory neurons reduced tactile over-reactivity in six distinct ASD models. Chronic treatment of Mecp2 and Shank3 mutant mice improved body condition, some brain abnormalities, anxiety-like behaviors, and some social impairments but not memory impairments, motor deficits, or overgrooming. Our findings reveal a potential therapeutic strategy targeting peripheral mechanosensory neurons to treat tactile over-reactivity and select ASD-related behaviors.


Assuntos
Transtorno do Espectro Autista/metabolismo , Agonistas GABAérgicos/farmacologia , Ácidos Isonicotínicos/farmacologia , Fenótipo , Células Receptoras Sensoriais/efeitos dos fármacos , Tato/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Ansiedade/tratamento farmacológico , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/genética , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Agonistas GABAérgicos/uso terapêutico , Ácidos Isonicotínicos/uso terapêutico , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas dos Microfilamentos , Proteínas do Tecido Nervoso/genética , Inibição Pré-Pulso/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo
7.
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
8.
J Neurosci ; 39(32): 6233-6250, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31182634

RESUMO

Dendritic spines in the developing mammalian neocortex are initially overproduced and then eliminated during adolescence to achieve appropriate levels of excitation in mature networks. We show here that the L1 family cell adhesion molecule Close Homolog of L1 (CHL1) and secreted repellent ligand Semaphorin 3B (Sema3B) function together to induce dendritic spine pruning in developing cortical pyramidal neurons. Loss of CHL1 in null mutant mice in both genders resulted in increased spine density and a greater proportion of immature spines on apical dendrites in the prefrontal and visual cortex. Electron microscopy showed that excitatory spine synapses with postsynaptic densities were increased in the CHL1-null cortex, and electrophysiological recording in prefrontal slices from mutant mice revealed deficiencies in excitatory synaptic transmission. Mechanistically, Sema3B protein induced elimination of spines on apical dendrites of cortical neurons cultured from wild-type but not CHL1-null embryos. Sema3B was secreted by the cortical neuron cultures, and its levels increased when cells were treated with the GABA antagonist gabazine. In vivo CHL1 was coexpressed with Sema3B in pyramidal neuron subpopulations and formed a complex with Sema3B receptor subunits Neuropilin-2 and PlexinA4. CHL1 and NrCAM, a closely related L1 adhesion molecule, localized primarily to distinct spines and promoted spine elimination to Sema3B or Sema3F, respectively. These results support a new concept in which selective spine elimination is achieved through different secreted semaphorins and L1 family adhesion molecules to sculpt functional neural circuits during postnatal maturation.SIGNIFICANCE STATEMENT Dendritic spines in the mammalian neocortex are initially overproduced and then pruned in adolescent life through unclear mechanisms to sculpt maturing cortical circuits. Here, we show that spine and excitatory synapse density of pyramidal neurons in the developing neocortex is regulated by the L1 adhesion molecule, Close Homolog of L1 (CHL1). CHL1 mediated spine pruning in response to the secreted repellent ligand Semaphorin 3B and associated with receptor subunits Neuropilin-2 and PlexinA4. CHL1 and related L1 adhesion molecule NrCAM localized to distinct spines, and promoted spine elimination to Semaphorin 3B and -3F, respectively. These results support a new concept in which selective elimination of individual spines and nascent synapses can be achieved through the action of distinct secreted semaphorins and L1 adhesion molecules.


Assuntos
Moléculas de Adesão Celular/fisiologia , Espinhas Dendríticas/fisiologia , Córtex Pré-Frontal/fisiologia , Semaforinas/fisiologia , Córtex Visual/fisiologia , Envelhecimento/fisiologia , Animais , Moléculas de Adesão Celular/deficiência , Células Cultivadas , Feminino , Agonistas GABAérgicos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/fisiologia , Neuropilina-2/fisiologia , Técnicas de Patch-Clamp , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/crescimento & desenvolvimento , Mapeamento de Interação de Proteínas , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Células Piramidais/ultraestrutura , Piridazinas/farmacologia , Receptores de Superfície Celular/fisiologia , Transmissão Sináptica , Córtex Visual/citologia , Córtex Visual/crescimento & desenvolvimento
9.
Bull Exp Biol Med ; 167(1): 39-42, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31177457

RESUMO

Voltage clamp and concentration-jump methods were employed to examine the effects of endogenous neuropeptide cycloprolylglycine on GABA-activated ionic currents in isolated cerebellar Purkinje cells. In the concentration range of 0.1-10.0 µM, short-term (600 msec) external application of cycloprolylglycine against the background of GABA-evoked current produced no effect on its amplitude. In contrast, application of 1 µM cycloprolylglycine increased current up to 177±15% control level. The development of potentiating effect and return to the control level of ionic current were slow, which was indicative of possible implication of second messenger systems in these processes. Functional augmentation of GABAA receptors under the action of cycloprolylglycine can underlie the established neuroprotective and anxiolytic effects of this endogenous dipeptide.


Assuntos
Peptídeos Cíclicos/farmacologia , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/metabolismo , Receptores de GABA-A/metabolismo , Animais , Células Cultivadas , Agonistas GABAérgicos/farmacologia , Humanos , Técnicas de Patch-Clamp , Peptídeos Cíclicos/metabolismo , Ratos
10.
Int J Neuropsychopharmacol ; 22(7): 453-465, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31188434

RESUMO

BACKGROUND: Synapsins are encoded by SYN I, SYN II, and SYN III, and they regulate neurotransmitter release by maintaining a reserve pool of synaptic vesicles. METHODS: Presynaptic dopamine responses to cocaine were examined by microdialysis, and postsynaptic responses were evaluated to various dopamine receptor agonists in the open field with SynI/SynII/SynIII triple knockout mice. RESULTS: Triple knockout mice showed enhanced spontaneous locomotion in a novel environment and were hyper-responsive to indirect and direct D1 and D2 dopamine agonists. Triple knockout animals appeared sensitized to cocaine upon first open field exposure; sensitization developed across days in wild-type controls. When mutants were preexposed to a novel environment before injection, cocaine-stimulated locomotion was reduced and behavioral sensitization retarded. Baseline dopamine turnover was enhanced in mutants and novel open field exposure increased their striatal dopamine synthesis rates. As KCl-depolarization stimulated comparable dopamine release in both genotypes, their readily releasable pools appeared indistinguishable. Similarly, cocaine-induced hyperlocomotion was indifferent to blockade of newly synthesized dopamine and depletion of releasable dopamine pools. Extracellular dopamine release was similar in wild-type and triple knockout mice preexposed to the open field and given cocaine or placed immediately into the arena following injection. Since motor effects to novelty and psychostimulants depend upon frontocortical-striatal inputs, we inhibited triple knockout medial frontal cortex with GABA agonists. Locomotion was transiently increased in cocaine-injected mutants, while their supersensitive cocaine response to novelty was lost. CONCLUSIONS: These results reveal presynaptic dopamine release is not indicative of agonist-induced triple knockout hyperlocomotion. Instead, their novelty response occurs primarily through postsynaptic mechanisms and network effects.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Agonistas de Dopamina/farmacologia , Dopamina/metabolismo , Atividade Motora/efeitos dos fármacos , Sinapses/metabolismo , Sinapsinas/deficiência , Animais , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Feminino , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Agonistas GABAérgicos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microdiálise , Atividade Motora/fisiologia , Sinapsinas/genética
11.
Curr Pediatr Rev ; 15(4): 251-258, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31241016

RESUMO

Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability with prevalence rates estimated to be 1:5,000 in males and 1:8,000 in females. The increase of >200 Cytosine Guanine Guanine (CGG) repeats in the 5' untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene results in transcriptional silencing on the FMR1 gene with a subsequent reduction or absence of fragile X mental retardation protein (FMRP), an RNA binding protein involved in the maturation and elimination of synapses. In addition to intellectual disability, common features of FXS are behavioral problems, autism, language deficits and atypical physical features. There are still no currently approved curative therapies for FXS, and clinical management continues to focus on symptomatic treatment of comorbid behaviors and psychiatric problems. Here we discuss several treatments that target the neurobiological pathway abnormal in FXS. These medications are clinically available at present and the data suggest that these medications can be helpful for those with FXS.


Assuntos
Síndrome do Cromossomo X Frágil/tratamento farmacológico , Agonistas GABAérgicos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Terapia de Alvo Molecular , Inibidores de Captação de Serotonina/farmacologia , Animais , Reprogramação Celular/genética , Criança , Metilação de DNA , Modelos Animais de Doenças , Epigênese Genética , Proteína do X Frágil de Retardo Mental , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Humanos , Terapia de Alvo Molecular/tendências , Transdução de Sinais , Resultado do Tratamento
12.
Eur Neuropsychopharmacol ; 29(4): 539-548, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30824339

RESUMO

Performance and conflict monitoring (PM and CM) represent two essential cognitive abilities, required to respond appropriately to demanding tasks. PM and CM can be investigated using event-related brain potentials (ERP) and associated neural oscillations. Namely, the error-related negativity (ERN) represents a correlate of PM, whereas the N2 component reflects the process of CM. Both ERPs originate in the anterior cingulate cortex (ACC) and PM specifically has been shown to be susceptible to gamma-aminobutyric acid (GABA) A receptor activation. Contrarily, the specific effects of GABAB receptor (GABABR) stimulation on PM and CM are unknown. Thus, the effects of gamma-hydroxybutyrate (GHB; 20 and 35 mg/kg), a predominant GABABR agonist, on behavioral and electrophysiological correlates of PM and CM were here assessed in 15 healthy male volunteers, using the Eriksen-Flanker paradigm in a randomized, double-blind, placebo-controlled, cross-over study. Electroencephalographic (EEG) data were analyzed in the time and time-frequency domains. GHB prolonged reaction times, without affecting error rates or post-error slowing. Moreover, GHB decreased ERN amplitudes and associated neural oscillations in the theta/alpha1 range. Similarly, neural oscillations associated with the N2 were reduced in the theta/alpha1 range, while N2 amplitude was conversely increased. Hence, GHB shows a dissociating effect on electrophysiological correlates of PM and CM. Reduced ERN likely derives from a GABABR-mediated increase in dopaminergic signaling, disrupting the generation of prediction errors, whereas an enhanced N2 suggests an increased susceptibility towards external stimuli. Conclusively, GHB is the first drug reported, thus far, to have opposite effects on PM and CM, underlined by its unique electrophysiological signature.


Assuntos
Cognição/fisiologia , Potenciais Evocados/efeitos dos fármacos , Oxibato de Sódio/farmacologia , Adolescente , Adulto , Ondas Encefálicas/efeitos dos fármacos , Estudos Cross-Over , Método Duplo-Cego , Eletroencefalografia , Agonistas GABAérgicos/farmacologia , Voluntários Saudáveis/psicologia , Humanos , Masculino , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Tempo de Reação/efeitos dos fármacos , Adulto Jovem
13.
Brain Res Bull ; 147: 110-123, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30797022

RESUMO

The key question to be answered in the present study was whether the medial septal GABAergic receptors are engaged in the pharmacological profile of the hippocampal formation (HPC) theta rhythm induced by vagal nerve stimulation (VNS). It was demonstrated that the medial septal microinfusion of GABAA and GABAB agonists (muscimol and baclofen) resulted in a progressive reduction of the power of VNS-induced theta. The medial septal microinfusion of GABAA and GABAB antagonists (bicuculline and 2-OH saclofen) resulted in the generation of VNS-induced theta with increased power. The effect of the combined medial septal microinfusion of GABAA agonist and antagonist and GABAB agonist and antagonist on VNS-induced theta rhythm was also evaluated: in the presence of GABAA,B antagonists the effect of agonists predominated. In separate experiments, GABAA and GABAB antagonists were administrated in anesthetized rats pretreated with i.v. administration of atropine sulfate. Atropine was found to abolish spontaneous theta and VNS-induced theta examined in the presence of bicuculline or 2-OH saclofen. The present data provide evidence that the medial septal GABAA and GABAB receptors are involved in the central mechanisms responsible for modulation of VNS-induced HPC theta oscillations. Furthermore, the results of the present study also demonstrate that, in fact, both GABAergic and cholinergic involvement is necessary for the appearance of VNS-induced theta.


Assuntos
Ritmo Teta/efeitos dos fármacos , Ritmo Teta/fisiologia , Nervo Vago/efeitos dos fármacos , Animais , Baclofeno/farmacologia , Bicuculina/farmacologia , Agonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/farmacologia , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Muscimol/farmacologia , Neurônios/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de GABA-A/fisiologia , Receptores de GABA-B/fisiologia , Estimulação do Nervo Vago/métodos , Ácido gama-Aminobutírico/farmacologia
14.
Neurobiol Learn Mem ; 159: 16-23, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30731234

RESUMO

Working memory (WM), the capacity for short-term storage and manipulation of small quantities of information, depends on fronto-parietal circuits. However, the function of the posterior parietal cortex (PPC) in WM has gone relatively understudied in rodents. Recent evidence calls into question whether the PPC is necessary for all forms of WM. Thus, the present experiment examined the role of the rat PPC in the Trial-Unique Non-matching-to-Location (TUNL) task, a touchscreen-based visuospatial WM task that relies on the rat medial prefrontal cortex (mPFC). Temporary inactivation of the PPC caused by bilateral infusions of muscimol and baclofen significantly impaired accuracy and increased the number of correction trials performed, indicating that the PPC is necessary for performance of TUNL. Additionally, we investigated the effects of blocking NMDA or non-NMDA parietal ionotropic glutamate receptors on TUNL and found that, in contrast to the prefrontal cortex, NMDA receptors in the PPC are not necessary for TUNL performance, whereas blockade of AMPA/Kainate receptors significantly impaired accuracy. These results indicate that performance of the TUNL task depends on the PPC but that NMDA receptor signaling within this brain area is not necessary for intact performance.


Assuntos
Comportamento Animal/fisiologia , Memória de Curto Prazo/fisiologia , Lobo Parietal/metabolismo , Desempenho Psicomotor/fisiologia , Receptores de AMPA/fisiologia , Receptores de Ácido Caínico/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Percepção Espacial/fisiologia , Percepção Visual/fisiologia , Animais , Baclofeno/farmacologia , Comportamento Animal/efeitos dos fármacos , Agonistas GABAérgicos/farmacologia , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Muscimol/farmacologia , Lobo Parietal/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Long-Evans , Receptores de AMPA/efeitos dos fármacos , Receptores de Ácido Caínico/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Percepção Espacial/efeitos dos fármacos , Percepção Visual/efeitos dos fármacos
15.
J Neurosci ; 39(6): 1077-1087, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30509960

RESUMO

Humans with alcohol use disorder typically abstain because of the negative consequences associated with excessive drinking, and exposure to contexts previously associated with alcohol use can trigger relapse. We used a rat model that captures a characteristic of this human condition: namely voluntary abstinence from alcohol use because of contingent punishment. There is substantial variability in the propensity to relapse following extended periods of abstinence, and this is a critical feature preventing the successful treatment of alcohol use disorder. Here we examined relapse following acute or prolonged abstinence. In male alcohol preferring P rats, we found an increased propensity to relapse in Context B, the punishment context after prolonged abstinence. Next, we found that neither alcohol intake history nor the motivational strength of alcohol predicted the propensity to relapse. We next examined the putative circuitry of context-induced relapse to alcohol seeking following prolonged abstinence using Fos as a marker of neuronal activation. The anterior insular cortex (AI) was the only brain region examined where Fos expression correlated with alcohol seeking behavior in Context B after prolonged abstinence. Finally, we used local infusion of GABAA and GABAB receptor agonists (muscimol + baclofen) to show a causal role of the AI in context-induced relapse in Context B, the punishment context after prolonged abstinence. Our results show that there is substantial individual variability in the propensity to relapse in the punishment-associated context after prolonged abstinence, and this is mediated by activity in the AI.SIGNIFICANCE STATEMENT A key feature of alcohol use disorder is that sufferers show an enduring propensity to relapse throughout their lifetime. Relapse typically occurs despite the knowledge of adverse consequences including health complications or relationship breakdowns. Here we use a recently developed rodent model that recapitulates this behavior. After an extended period of abstinence, relapse propensity is markedly increased in the "adverse consequence" environment, akin to humans with alcohol use disorder relapsing in the face of adversity. From a circuitry perspective, we demonstrate a causal role of the anterior insular cortex in relapse to alcohol seeking after extended abstinence following punishment imposed voluntary cessation of alcohol use.


Assuntos
Abstinência de Álcool/psicologia , Consumo de Bebidas Alcoólicas/psicologia , Córtex Cerebral/fisiologia , Comportamento de Procura de Droga/fisiologia , Punição/psicologia , Animais , Depressores do Sistema Nervoso Central/farmacologia , Córtex Cerebral/efeitos dos fármacos , Comportamento de Procura de Droga/efeitos dos fármacos , Etanol/farmacologia , Agonistas GABAérgicos/farmacologia , Agonistas dos Receptores de GABA-B/farmacologia , Genes fos/genética , Masculino , Motivação , Ratos , Receptores de GABA-A/efeitos dos fármacos , Recidiva
16.
J Neurosci ; 39(6): 1058-1065, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30541909

RESUMO

Nigrostriatal dopamine (DA) is critical to action selection and learning. Axonal DA release is locally influenced by striatal neurotransmitters. Striatal neurons are principally GABAergic projection neurons and interneurons, and a small minority of other neurons are cholinergic interneurons (ChIs). ChIs strongly gate striatal DA release via nicotinic receptors (nAChRs) identified on DA axons. Striatal GABA is thought to modulate DA, but GABA receptors have not been documented conclusively on DA axons. However, ChIs express GABA receptors and are therefore candidates for potential mediators of GABA regulation of DA. We addressed whether striatal GABA and its receptors can modulate DA release directly, independently from ChI regulation, by detecting DA in striatal slices from male mice using fast-scan cyclic voltammetry in the absence of nAChR activation. DA release evoked by single electrical pulses in the presence of the nAChR antagonist dihydro-ß-erythroidine was reduced by GABA or agonists of GABAA or GABAB receptors, with effects prevented by selective GABA receptor antagonists. GABA agonists slightly modified the frequency sensitivity of DA release during short stimulus trains. GABA agonists also suppressed DA release evoked by optogenetic stimulation of DA axons. Furthermore, antagonists of GABAA and GABAB receptors together, or GABAB receptors alone, significantly enhanced DA release evoked by either optogenetic or electrical stimuli. These results indicate that striatal GABA can inhibit DA release through GABAA and GABAB receptors and that these actions are not mediated by cholinergic circuits. Furthermore, these data reveal that there is a tonic inhibition of DA release by striatal GABA operating through predominantly GABAB receptors.SIGNIFICANCE STATEMENT The principal inhibitory transmitter in the mammalian striatum, GABA, is thought to modulate striatal dopamine (DA) release, but definitive evidence for GABA receptors on DA axons is lacking. Striatal cholinergic interneurons regulate DA release via axonal nicotinic receptors (nAChRs) and also express GABA receptors, but they have not been eliminated as potentially critical mediators of DA regulation by GABA. Here, we found that GABAA and GABAB receptors inhibit DA release without requiring cholinergic interneurons. Furthermore, ambient levels of GABA inhibited DA release predominantly through GABAB receptors. These findings provide further support for direct inhibition of DA release by GABA receptors and reveal that striatal GABA operates a tonic inhibition on DA output that could critically influence striatal output.


Assuntos
Corpo Estriado/metabolismo , Dopamina/metabolismo , Receptores de GABA-A/metabolismo , Receptores de GABA-B/metabolismo , Substância Negra/metabolismo , Animais , Axônios/metabolismo , Antagonistas Colinérgicos/farmacologia , Di-Hidro-beta-Eritroidina/farmacologia , Estimulação Elétrica , Agonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Optogenética , Sistema Nervoso Parassimpático/efeitos dos fármacos , Sistema Nervoso Parassimpático/metabolismo , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-B/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo
17.
J Neurotrauma ; 36(10): 1632-1645, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30484362

RESUMO

Traumatic brain injuries (TBI) lead to dramatic changes in the surviving brain tissue. Altered ion concentrations, coupled with changes in the expression of membrane-spanning proteins, create a post-TBI brain state that can lead to further neuronal loss caused by secondary excitotoxicity. Several GABA receptor agonists have been tested in the search for neuroprotection immediately after an injury, with paradoxical results. These drugs not only fail to offer neuroprotection, but can also slow down functional recovery after TBI. Here, using computational modeling, we provide a biophysical hypothesis to explain these observations. We show that the accumulation of intracellular chloride ions caused by a transient upregulation of Na+-K+-2Cl- (NKCC1) co-transporters as observed following TBI, causes GABA receptor agonists to lead to excitation and depolarization block, rather than the expected hyperpolarization. The likelihood of prolonged, excitotoxic depolarization block is further exacerbated by the extremely high levels of extracellular potassium seen after TBI. Our modeling results predict that the neuroprotective efficacy of GABA receptor agonists can be substantially enhanced when they are combined with NKCC1 co-transporter inhibitors. This suggests a rational, biophysically principled method for identifying drug combinations for neuroprotection after TBI.


Assuntos
Lesões Encefálicas Traumáticas , Simulação por Computador , Agonistas GABAérgicos/farmacologia , Modelos Neurológicos , Fármacos Neuroprotetores/farmacologia , Células Piramidais/efeitos dos fármacos , Animais , Humanos , Células Piramidais/fisiologia
18.
J Pharmacol Exp Ther ; 368(1): 100-105, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30389723

RESUMO

Central α4ßδ receptors are the most abundant isoform of δ subunit-containing extrasynaptic GABAA receptors that mediate tonic inhibition. Although the amplitude of GABA-activated currents through α4ßδ receptors is modulated by multiple general anesthetics, the effects of general anesthetics on desensitization and deactivation of α4ßδ receptors remain unknown. In the current study, we investigated the effect of etomidate, a potent general anesthetic, on the kinetics and the pseudo steady-state current amplitude of α4ß3δ receptors inducibly expressed in human embryonic kidney 293 TetR cells. Etomidate directly activates α4ß3δ receptors in a concentration-dependent manner. Etomidate at a clinically relevant concentration (3.2 µM) enhances maximal response without altering the EC50 of GABA concentration response. Etomidate also increases the extent of desensitization and prolongs the deactivation of α4ß3δ receptors in the presence of maximally activating concentrations of GABA (1 mM). To mimic the modulatory effect of etomidate on tonic currents, long pulses (30-60 seconds) of a low GABA concentration (1 µM) were applied to activate α4ß3δ receptors in the absence and presence of etomidate. Although etomidate increases the desensitization of α4ß3δ receptors, the pseudo steady-state current amplitude at 1 µM GABA is augmented by etomidate. Our data demonstrate that etomidate enhances the pseudo steady-state current of α4ß3δ receptors evoked by a GABA concentration comparable to an ambient GABA level, suggesting that α4ß3δ receptors may mediate etomidate's anesthetic effect in the brain.


Assuntos
Etomidato/farmacologia , Agonistas GABAérgicos/farmacologia , Hipnóticos e Sedativos/farmacologia , Receptores de GABA-A/biossíntese , Relação Dose-Resposta a Droga , Expressão Gênica , Células HEK293 , Humanos , Receptores de GABA-A/genética , Ácido gama-Aminobutírico/farmacologia
19.
Mol Pharmacol ; 95(1): 70-81, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30337372

RESUMO

Under both physiologic and clinical conditions GABAA receptors are exposed to multiple agonists, including the transmitter GABA, endogenous or exogenous neuroactive steroids, and various GABAergic anesthetic and sedative drugs. The functional output of the receptor reflects the interplay among all active agents. We have investigated the activation of the concatemeric α1ß2γ2L GABAA receptor by combinations of agonists. Simulations of receptor activity using the coagonist concerted transition model demonstrate that the response amplitude in the presence of agonist combinations is highly dependent on whether the paired agonists interact with the same or distinct sites. The experimental data for receptor activation by agonist combinations were in agreement with the established views of the overlap of binding sites for several pairs of orthosteric (GABA, ß-alanine, and piperidine-4-sulfonic acid) and/or allosteric agents (propofol, pentobarbital, and several neuroactive steroids). Conversely, the degree of potentiation when two GABAergic agents are coapplied can be used to determine whether the compounds act by binding to the same or distinct sites. We show that common interaction sites mediate the actions of 5α- and 5ß-reduced neuroactive steroids, and natural and enantiomeric steroids. Furthermore, the results indicate that the anesthetics propofol and pentobarbital interact with partially shared binding sites. We propose that the findings may be used to predict the efficacy of drug mixtures in combination therapy and thus have potential clinical relevance.


Assuntos
Sítios de Ligação/efeitos dos fármacos , Agonistas GABAérgicos/farmacologia , Receptores de GABA-A/metabolismo , Regulação Alostérica/efeitos dos fármacos , Anestésicos/farmacologia , Animais , Neurotransmissores/metabolismo , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Pentobarbital/farmacologia , Propofol/farmacologia , Xenopus laevis , Ácido gama-Aminobutírico/metabolismo
20.
J Neurosci ; 39(2): 224-237, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30459224

RESUMO

The input-output relationships in neural circuits are determined not only by synaptic efficacy but also by neuronal excitability. Activity-dependent alterations of synaptic efficacy have been extensively investigated, but relatively less is known about how the neuronal output is modulated when synaptic efficacy changes are associated with neuronal excitability changes. In this study, we demonstrate that paired pulses of low-frequency stimulation (PP-LFS) induced metabotropic glutamate receptor (mGluR)-dependent LTD at Schaffer collateral (SC)-CA1 synapses in Sprague Dawley rats (both sexes), and this LTD was associated with EPSP to spike (E-S) potentiation, leading to the increase in action potential (AP) outputs. Threshold voltage (Vth) for APs evoked by synaptic stimulation and that by somatic current injection were hyperpolarized significantly after PP-LFS. Blockers of GABA receptors mimicked and occluded PP-LFS effects on E-S potentiation and Vth hyperpolarization, suggesting that suppression of GABAergic mechanisms is involved in E-S potentiation after PP-LFS. Indeed, IPSCs and tonic inhibitory currents were reduced after PP-LFS. The IPSC reduction was accompanied by increased paired-pulse ratio, and abolished by AM251, a blocker for Type 1 cannabinoid receptors, suggesting that PP-LFS suppresses presynaptic GABA release by mGluR-dependent endocannabinoids signaling. By contrast, a Group 1 mGluR agonist, 3, 5-dihydroxyphenylglycine, induced LTD at SC-CA1 synapses but failed to induce significant IPSC reduction and AP output increase. We propose that mGluR signaling that induces LTD coexpression at excitatory and inhibitory synapses regulates an excitation-inhibition balance to increase neuronal output in CA1 neurons.SIGNIFICANCE STATEMENT Long-lasting forms of synaptic plasticity are usually associated with excitability changes, the ability to fire action potentials. However, excitability changes have been regarded to play subsidiary roles to synaptic plasticity in modifying neuronal output. We demonstrate that, when metabotropic glutamate receptor-dependent LTD is induced by paired pulses of low-frequency stimulation, the action potential output in response to a given input paradoxically increases, indicating that increased excitability is more powerful than synaptic depression. This increase is mediated by the suppression of a presynaptic GABA release via metabotropic glutamate receptor-dependent endocannabinoid signaling. Our study shows that neuronal output changes do not always follow the direction of synaptic plasticity at excitatory synapses, highlighting the importance of regulating inhibitory tone via endocannabinoid signaling.


Assuntos
Região CA1 Hipocampal/fisiologia , Endocanabinoides/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Células Piramidais/fisiologia , Receptores de Glutamato Metabotrópico/metabolismo , Sinapses/fisiologia , Potenciais de Ação/fisiologia , Animais , Região CA1 Hipocampal/citologia , Antagonistas de Receptores de Canabinoides/farmacologia , Feminino , Agonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/farmacologia , Masculino , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley
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