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1.
Adv Pharmacol ; 89: 3-41, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616211

RESUMO

A single sub-anesthetic intravascular dose of the use-dependent NMDAR antagonist, ketamine, improves mood in patients with treatment resistant depression within hours that can last for days, creating an entirely new treatment strategy for the most seriously ill patients. However, the psychomimetic effects and abuse potential of ketamine require that new therapies be developed that maintain the rapid antidepressant effects of ketamine without the unwanted side effects. This necessitates a detailed understanding of what cellular and synaptic mechanisms are immediately activated once ketamine reaches the brain that triggers the needed changes to elicit the improved behavior. Intense research has centered on the effects of ketamine, and the other rapidly acting antidepressants, on excitatory and inhibitory circuits in hippocampus and medial prefrontal cortex to determine common mechanisms, including key modifications in synaptic transmission and the precise location of the NMDARs that mediate the rapid and sustained antidepressant response. We review data comparing the effects of ketamine with other NMDAR receptor modulators and the muscarinic M1 acetylcholine receptor antagonist, scopolamine, together with evidence supporting the disinhibition hypothesis and the direct inhibition hypothesis of ketamine's mechanism of action on synaptic circuits using preclinical models.


Assuntos
Antidepressivos/farmacologia , Hipocampo/fisiologia , Ketamina/farmacologia , Inibição Neural/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Hipocampo/efeitos dos fármacos , Humanos , Ketamina/administração & dosagem , Ketamina/uso terapêutico , Caracteres Sexuais
2.
Adv Pharmacol ; 89: 43-78, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616214

RESUMO

There has been much recent progress in understanding of the mechanism of ketamine's rapid and enduring antidepressant effects. Here we review recent insights from clinical and preclinical studies, with special emphasis of ketamine-induced changes in GABAergic synaptic transmission that are considered essential for its antidepressant therapeutic effects. Subanesthetic ketamine is now understood to exert its initial action by selectively blocking a subset of NMDA receptors on GABAergic interneurons, which results in disinhibition of glutamatergic target neurons, a surge in extracellular glutamate and correspondingly elevated glutamatergic synaptic transmission. This surge in glutamate appears to be corroborated by the rapid metabolism of ketamine into hydroxynorketamine, which acts at presynaptic sites to disinhibit the release of glutamate. Preclinical studies indicate that glutamate-induced activity triggers the release of BDNF, followed by transient activation of the mTOR pathway and increased expression of synaptic proteins, along with functional strengthening of glutamatergic synapses. This drug-on phase lasts for approximately 2h and is followed by a period of days characterized by structural maturation of newly formed glutamatergic synapses and prominently enhanced GABAergic synaptic inhibition. Evidence from mouse models with constitutive antidepressant-like phenotypes suggests that this phase involves strengthened inhibition of dendrites by somatostatin-positive GABAergic interneurons and correspondingly reduced NMDA receptor-mediated Ca2+ entry into dendrites, which activates an intracellular signaling cascade that converges with the mTOR pathway onto increased activity of the eukaryotic elongation factor eEF2 and enhanced translation of dendritic mRNAs. Newly synthesized proteins such as BDNF may be important for the prolonged therapeutic effects of ketamine.


Assuntos
Antidepressivos/farmacologia , Neurônios GABAérgicos/fisiologia , Ketamina/farmacologia , Inibição Neural/efeitos dos fármacos , Animais , Depressão/fisiopatologia , Neurônios GABAérgicos/efeitos dos fármacos , Humanos , Metaboloma/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos
3.
Chem Biol Interact ; 328: 109144, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32653415

RESUMO

The debilitating nature of cognitive impairment in epilepsy and the potential of some traditional antiepileptics to further deteriorate cognitive function are areas of growing concern. Glucagon-like peptide-1 (GLP-1) deficiency has been linked to reduced seizure threshold as well as cognitive dysfunction. Here, we tested whether sitagliptin (SITA), by virtue of its neuroprotective properties, could alleviate both epilepsy and associated cognitive dysfunction in a rat model of kindling epilepsy. Chemical kindling was induced by subconvulsive doses of pentylenetetrazol (PTZ) (30 mg/kg; i.p). SITA (50 mg/kg; p.o) was administered 1 h before PTZ injections. SITA conceivably attenuated PTZ hippocampal histological insult, preserved neuronal integrity and amended neurotransmitter perturbations in rat hippocampi paralleled with enhanced hippocampal GLP-1 levels as well as the downstream cAMP content and protein kinase A (PKA) activity. Moreover, SITA improved cognitive functioning of rats in the Morris water maze which was coupled with hampered hippocampal p(Ser404)-tau and ß-amyloid proteins. SITA replenished p(Ser9)-glycogen synthase kinase-3ß (GSK-3ß). It also opposed the boosted matrix metalloproteinase-9 (MMP-9), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor-1 (IGF-1) levels associated with PTZ administration along with mitigation of both ß-secretase-1 (BACE1) immunoreactivity and receptor for advanced glycation end products (RAGE) protein level in rat hippocampi. In conclusion, SITA subdues epileptic and cognitive upshots of PTZ kindling in rats, which might correspond to the modulation of BACE1, amyloidogenic/RAGE axis as well as GSK-3ß/MMP-9/BDNF signaling cascade. SITA effects are probably mediated via boosting GLP-1 and subsequently enhancing GLP-1/GLP-1R signaling.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/metabolismo , Excitação Neurológica/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais , Fosfato de Sitagliptina/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Biomarcadores/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtornos Cognitivos/patologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Inibição Neural/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Neurotransmissores/metabolismo , Pentilenotetrazol , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/metabolismo , Convulsões/patologia , Transdução de Sinais/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Proteínas tau/metabolismo
4.
J Neurosci ; 40(17): 3348-3359, 2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-32169968

RESUMO

Nitric oxide (NO) is an important signaling molecule that fulfills diverse functional roles as a neurotransmitter or diffusible second messenger in the developing and adult CNS. Although the impact of NO on different behaviors such as movement, sleep, learning, and memory has been well documented, the identity of its molecular and cellular targets is still an area of ongoing investigation. Here, we identify a novel role for NO in strengthening inhibitory GABAA receptor-mediated transmission in molecular layer interneurons of the mouse cerebellum. NO levels are elevated by the activity of neuronal NO synthase (nNOS) following Ca2+ entry through extrasynaptic NMDA-type ionotropic glutamate receptors (NMDARs). NO activates protein kinase G with the subsequent production of cGMP, which prompts the stimulation of NADPH oxidase and protein kinase C (PKC). The activation of PKC promotes the selective strengthening of α3-containing GABAARs synapses through a GΑΒΑ receptor-associated protein-dependent mechanism. Given the widespread but cell type-specific expression of the NMDAR/nNOS complex in the mammalian brain, our data suggest that NMDARs may uniquely strengthen inhibitory GABAergic transmission in these cells through a novel NO-mediated pathway.SIGNIFICANCE STATEMENT Long-term changes in the efficacy of GABAergic transmission is mediated by multiple presynaptic and postsynaptic mechanisms. A prominent pathway involves crosstalk between excitatory and inhibitory synapses whereby Ca2+-entering through postsynaptic NMDARs promotes the recruitment and strengthening of GABAA receptor synapses via Ca2+/calmodulin-dependent protein kinase II. Although Ca2+ transport by NMDARs is also tightly coupled to nNOS activity and NO production, it has yet to be determined whether this pathway affects inhibitory synapses. Here, we show that activation of NMDARs trigger a NO-dependent pathway that strengthens inhibitory GABAergic synapses of cerebellar molecular layer interneurons. Given the widespread expression of NMDARs and nNOS in the mammalian brain, we speculate that NO control of GABAergic synapse efficacy may be more widespread than has been appreciated.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Cerebelo/metabolismo , Interneurônios/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Óxido Nítrico/metabolismo , Transdução de Sinais/fisiologia , Animais , Cerebelo/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Interneurônios/efeitos dos fármacos , Masculino , Camundongos , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Técnicas de Patch-Clamp , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
5.
Sci Rep ; 10(1): 962, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969605

RESUMO

Long-term memory of complex olfactory learning is expressed by wide spread enhancement in excitatory and inhibitory synaptic transmission onto piriform cortex pyramidal neurons. A particularly interesting modification in synaptic inhibition is the hyperpolarization of the reversal potential of the fast post synaptic inhibitory potential (fIPSP). Here we study the mechanism underlying the maintenance of such a shift in the fIPSP. Blocking of the neuronal specific K+-Cl- co-transporter (KCC2) in neurons of trained rats significantly depolarized the averaged fIPSP reversal potential of the spontaneous miniature inhibitory post synaptic currents (mIPSCs), to the averaged pre-training level. A similar effect was obtained by blocking PKC, which was previously shown to upregulate KCC2. Accordingly, the level of PKC-dependent phosphorylation of KCC2, at the serine 940 site, was significantly increased after learning. In contrast, blocking two other key second messenger systems CaMKII and PKA, which have no phosphorylation sites on KCC2, had no effect on the fIPSP reversal potential. Importantly, the PKC inhibitor also reduced the averaged amplitude of the spontaneous miniature excitatory synaptic currents (mEPSCs) in neurons of trained rats only, to the pre-training level. We conclude that learning-induced hyper-polarization of the fIPSP reversal potential is mediated by PKC-dependent increase of KCC2 phosphorylation.


Assuntos
Aprendizagem por Discriminação/fisiologia , Inibição Neural/fisiologia , Proteína Quinase C/metabolismo , Simportadores/metabolismo , Sinapses/metabolismo , Regulação para Cima/efeitos dos fármacos , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Aprendizagem por Discriminação/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Masculino , Potenciais Pós-Sinápticos em Miniatura/efeitos dos fármacos , Potenciais Pós-Sinápticos em Miniatura/fisiologia , Inibição Neural/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosforilação/efeitos dos fármacos , Proteína Quinase C/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Olfato/efeitos dos fármacos , Olfato/fisiologia , Simportadores/antagonistas & inibidores , Sinapses/efeitos dos fármacos
6.
Pain ; 160(6): 1448-1458, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31107414

RESUMO

Diabetic neuropathy is an incapacitating complication in diabetic patients. The cellular and molecular mechanisms involved in this pathology are poorly understood. Previous studies have suggested that the loss of spinal GABAergic inhibition participate in painful diabetic neuropathy. However, the role of extrasynaptic α5 subunit-containing GABAA (α5GABAA) receptors in this process is not known. The purpose of this study was to investigate the role of α5GABAA receptors in diabetes-induced tactile allodynia, loss of rate-dependent depression (RDD) of the Hoffmann reflex (HR), and modulation of primary afferent excitability. Intraperitoneal administration of streptozotocin induced tactile allodynia. Intrathecal injection of α5GABAA receptor inverse agonist, L-655,708, produced tactile allodynia in naive rats, whereas it reduced allodynia in diabetic rats. In healthy rats, electrical stimulation of the tibial nerve at 5 Hz induced RDD of the HR, although intrathecal treatment with L-655,708 (15 nmol) abolished RDD of the HR. Streptozotocin induced the loss of RDD of the HR, while intrathecal L-655,708 (15 nmol) restored RDD of the HR. L-655,708 (15 nmol) increased tonic excitability of the primary afferents without affecting the phasic excitability produced by the primary afferent depolarization. α5GABAA receptors were immunolocalized in superficial laminae of the dorsal horn and L4 to L6 dorsal root ganglion. Streptozotocin increased mean fluorescence intensity and percentage of neurons expressing α5GABAA receptors in dorsal horn and L4 to L6 dorsal root ganglia in 10-week diabetic rats. Our results suggest that spinal α5GABAA receptors modulate the HR, play an antinociceptive and pronociceptive role in healthy and diabetic rats, respectively, and are tonically active in primary afferents.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Agonistas de Receptores de GABA-A/farmacologia , Receptores de GABA-A/efeitos dos fármacos , Reflexo/efeitos dos fármacos , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Proteínas de Transporte/metabolismo , Diabetes Mellitus Experimental/complicações , Neuropatias Diabéticas/complicações , Neuropatias Diabéticas/tratamento farmacológico , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/patologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/etiologia , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Ratos Wistar , Reflexo/fisiologia , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Corno Dorsal da Medula Espinal/patologia
7.
Int J Neuropsychopharmacol ; 22(7): 435-444, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31095686

RESUMO

BACKGROUND: The goal of this study was to examine baseline transcranial magnetic stimulation measures of cortical inhibition and excitability in depressed patients and characterize their longitudinal posttreatment changes. METHODS: Fifteen adolescents (age 13-17 years) with moderate to severe major depressive disorder and 22 healthy controls (age 9-17) underwent single- and paired-pulse transcranial magnetic stimulation and clinical assessments. Transcranial magnetic stimulation measures included short-interval intracortical inhibition (2 and 4 milliseconds), long-interval intracortical inhibition (100, 150, and 200 milliseconds), cortical silent period, and intracortical facilitation (10, 15, and 20 milliseconds). Ten participants with major depressive disorder initiated antidepressant treatment or had dose adjustments. These participants were reassessed after treatment. Depression symptom severity was measured with the Children's Depression Rating Scale, Revised. Robust regression modeling compared healthy and depressed adolescents at baseline. Relationships between changes in cortical inhibition and changes in depressive symptom severity were assessed in the depressed adolescents receiving antidepressant treatment. RESULTS: Our results revealed that at baseline, short-interval intracortical inhibition-2 was significantly reduced (Padj = .01) in depressed participants, suggesting impaired cortical inhibition compared with healthy controls. At follow-up, improvement in Children's Depression Rating Scale, Revised scores correlated with improvement in short-interval intracortical inhibition-4 amplitude (greater inhibition) after antidepressant treatment (R2 = 0.63; P = .01). CONCLUSIONS: These results suggest that cortical inhibition measures may have promise as biomarkers in adolescents treated for depression.


Assuntos
Antidepressivos/uso terapêutico , Encéfalo/efeitos dos fármacos , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/tratamento farmacológico , Inibição Neural/efeitos dos fármacos , Estimulação Magnética Transcraniana , Adolescente , Encéfalo/fisiopatologia , Criança , Transtorno Depressivo Maior/fisiopatologia , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Inibição Neural/fisiologia , Escalas de Graduação Psiquiátrica , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Estimulação Magnética Transcraniana/métodos , Resultado do Tratamento
8.
Mol Brain ; 12(1): 29, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30935412

RESUMO

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressant drugs in pregnant women. Infants born following prenatal exposure to SSRIs have a higher risk for behavioral abnormalities, however, the underlying mechanisms remains unknown. Therefore, we examined the effects of prenatal fluoxetine, the most commonly prescribed SSRI, in mice. Intriguingly, chronic in utero fluoxetine treatment impaired working memory and social novelty recognition in adult males. In the medial prefrontal cortex (mPFC), a key region regulating these behaviors, we found augmented spontaneous inhibitory synaptic transmission onto the layer 5 pyramidal neurons. Fast-spiking interneurons in mPFC exhibited enhanced intrinsic excitability and serotonin-induced excitability due to upregulated serotonin (5-HT) 2A receptor (5-HT2AR) signaling. More importantly, the behavioral deficits in prenatal fluoxetine treated mice were reversed by the application of a 5-HT2AR antagonist. Taken together, our findings suggest that alterations in inhibitory neuronal modulation are responsible for the behavioral alterations following prenatal exposure to SSRIs.


Assuntos
Memória de Curto Prazo/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Reconhecimento Psicológico/efeitos dos fármacos , Inibidores de Captação de Serotonina/efeitos adversos , Comportamento Social , Sinapses/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Comportamento Animal , Feminino , Fluoxetina/efeitos adversos , Interneurônios/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Inibição Neural/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Antagonistas da Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Sinapses/efeitos dos fármacos
9.
Glia ; 67(6): 1076-1093, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30801845

RESUMO

G protein-coupled receptors (GPCRs) play key roles in intercellular signaling in the brain. Their effects on cellular function have been largely studied in neurons, but their functional consequences on astrocytes are less known. Using both endogenous and chemogenetic approaches with DREADDs, we have investigated the effects of Gq and Gi/o GPCR activation on astroglial Ca2+ -based activity, gliotransmitter release, and the functional consequences on neuronal electrical activity. We found that while Gq GPCR activation led to cellular activation in both neurons and astrocytes, Gi/o GPCR activation led to cellular inhibition in neurons and cellular activation in astrocytes. Astroglial activation by either Gq or Gi/o protein-mediated signaling stimulated gliotransmitter release, which increased neuronal excitability. Additionally, activation of Gq and Gi/o DREADDs in vivo increased astrocyte Ca2+ activity and modified neuronal network electrical activity. Present results reveal additional complexity of the signaling consequences of excitatory and inhibitory neurotransmitters in astroglia-neuron network operation and brain function.


Assuntos
Astrócitos/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Inibição Neural/fisiologia , Neuroglia/metabolismo , Neurônios/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Feminino , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/agonistas , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Antagonistas Muscarínicos/farmacologia , Inibição Neural/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/metabolismo
10.
Neuropharmacology ; 148: 358-365, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30721695

RESUMO

Glycine receptors (GlyRs) are pentameric proteins that consist of α (α1-α4) subunits and/or ß subunit. In the spinal cord of adult animals, the majority of inhibitory glycinergic neurotransmission is mediated by α1 subunit-containing GlyRs. The reduced glycinergic inhibition (disinhibition) is proposed to increase the excitabilities and spontaneous activities of spinal nociceptive neurons during pathological pain. However, the molecular mechanisms by which peripheral lesions impair GlyRs-α1-mediated synaptic inhibition remain largely unknown. Here we found that activity-dependent ubiquitination of GlyRs-α1 subunit might contribute to glycinergic disinhibition after peripheral inflammation. Our data showed that HUWE1 (HECT, UBA, WWE domain containing 1), an E3 ubiquitin ligase, located at spinal synapses and specifically interacted with GlyRs-α1 subunit. By ubiquitinating GlyRs-α1, HUWE1 reduced the surface expression of GlyRs-α1 through endocytic pathway. In the dorsal horn of Complete Freund's Adjuvant-injected mice, shRNA-mediated knockdown of HUWE1 blunted GlyRs-α1 ubiquitination, potentiated glycinergic synaptic transmission and attenuated inflammatory pain. These data implicated that ubiquitin modification of GlyRs-α1 represented an important way for peripheral inflammation to reduce spinal glycinergic inhibition and that interference with HUWE1 activity generated analgesic action by resuming GlyRs-α1-mediated synaptic transmission.


Assuntos
Inibição Neural/fisiologia , Receptores da Glicina/fisiologia , Corno Dorsal da Medula Espinal/fisiopatologia , Proteínas Supressoras de Tumor/fisiologia , Ubiquitina-Proteína Ligases/fisiologia , Ubiquitinação/efeitos dos fármacos , Animais , Células Cultivadas , Humanos , Masculino , Camundongos , Inibição Neural/efeitos dos fármacos , Dor/prevenção & controle , RNA Interferente Pequeno/farmacologia , Receptores da Glicina/efeitos dos fármacos , Receptores da Glicina/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/farmacologia , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/farmacologia
11.
Neurosci Lett ; 699: 145-150, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-30742935

RESUMO

Inhibitory circuits in the auditory brainstem undergo multiple postnatal changes that are both activity-dependent and activity-independent. We tested to see if the shift from GABA- to glycinergic transmission, which occurs in the rat medial nucleus of the trapezoid body (MNTB) around the onset of hearing, depends on sound-evoked neuronal activity. We prevented the activity by bilateral cochlear ablations in early postnatal rats and studied ionotropic GABA and glycine receptors in MNTB neurons after hearing onset. The removal of the cochlea decreased responses of GABAA and glycine receptors to exogenous agonists as well as the amplitudes of inhibitory postsynaptic currents. The reduction was accompanied by a decrease in the number of glycine receptor- or vesicular GABA transporter-immunopositive puncta. Furthermore, the ablations markedly affected the switch in presynaptic GABAA to glycine receptors. The increase in the expression of postsynaptic glycine receptors and the shift in inhibitory transmitters were not prevented. The results suggest that inhibitory transmission in the MNTB is subject to multiple developmental signals and support the idea that auditory experience plays a role in the maturation of the brainstem glycinergic circuits.


Assuntos
Técnicas de Ablação , Cóclea/fisiopatologia , Cóclea/cirurgia , Inibição Neural/fisiologia , Transmissão Sináptica , Corpo Trapezoide/fisiologia , Animais , Animais Recém-Nascidos , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Agonistas de Receptores de GABA-A/farmacologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Masculino , Inibição Neural/efeitos dos fármacos , Ratos , Receptores de GABA-A/fisiologia , Receptores da Glicina/agonistas , Receptores da Glicina/metabolismo , Receptores da Glicina/fisiologia , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismo
12.
Neuropsychopharmacology ; 44(6): 1114-1122, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30758322

RESUMO

The nucleus accumbens is a critical integration center for reward-related circuitry and is comprised primarily of medium spiny projection neurons. The dynamic balance of excitation and inhibition onto medium spiny neurons determines the output of this structure. While nucleus accumbens excitatory synaptic plasticity is well-characterized, inhibitory synaptic plasticity mechanisms and their potential relevance to shaping motivated behaviors is poorly understood. Here we report the discovery of long-term depression of inhibitory synaptic transmission in the mouse nucleus accumbens core. This long-term depression is postsynaptically expressed, tropomyosin kinase B (TrkB) receptor-mediated, and augmented in the presence of ethanol. Our findings support the emerging view that TrkB signaling regulates inhibitory synaptic plasticity and suggest this mechanism in the nucleus accumbens as a target for ethanol modulation of reward.


Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Depressão Sináptica de Longo Prazo , Glicoproteínas de Membrana/metabolismo , Inibição Neural , Núcleo Accumbens , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais , Animais , Feminino , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Depressão Sináptica de Longo Prazo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
13.
Pain ; 160(4): 805-823, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30681984

RESUMO

Stability of local medial prefrontal cortex (mPFC) network activity is believed to be critical for sustaining cognitive processes such as working memory (WM) and decision making. Dysfunction of the mPFC has been identified as a leading cause to WM deficits in several chronic pain conditions; however, the underlying mechanisms remain largely undetermined. Here, to address this issue, we implanted multichannel arrays of electrodes in the prelimbic region of the mPFC and recorded the neuronal activity during a food-reinforced delayed nonmatch to sample (DNMS) task of spatial WM. In addition, we used an optogenetic technique to selectively suppress the activity of excitatory pyramidal neurons that are considered the neuronal substrate for memory retention during the delay period of the behavioral task. Within-subject behavioral performance and pattern of neuronal activity were assessed after the onset of persistent pain using the spared nerve injury model of peripheral neuropathy. Our results show that the nerve lesion caused a disruption in WM and prelimbic spike activity and that this disruption was reversed by the selective inhibition of prelimbic glutamatergic pyramidal neurons during the delay period of the WM task. In spared nerve injury animals, photoinhibition of excitatory neurons improved the performance level and restored neural activity to a similar profile observed in the control animals. In addition, we found that selective inhibition of excitatory neurons does not produce antinociceptive effects. Together, our findings suggest that disruption of balance in local prelimbic networks may be crucial for the neurological and cognitive deficits observed during painful syndromes.


Assuntos
Glutamatos/metabolismo , Transtornos da Memória/etiologia , Transtornos da Memória/terapia , Neuralgia/complicações , Optogenética/métodos , Córtex Pré-Frontal/citologia , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Comportamento de Escolha/fisiologia , Modelos Animais de Doenças , Potenciais Evocados/fisiologia , Humanos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Memória de Curto Prazo/fisiologia , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Tempo de Reação/fisiologia , Transdução Genética
14.
Pain ; 160(4): 824-832, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30681985

RESUMO

Chronic pain is associated with neuroplastic changes in the amygdala that may promote hyper-responsiveness to mechanical and thermal stimuli (allodynia and hyperalgesia) and/or enhance emotional and affective consequences of pain. Stress promotes dynorphin-mediated signaling at the kappa opioid receptor (KOR) in the amygdala and mechanical hypersensitivity in rodent models of functional pain. Here, we tested the hypothesis that KOR circuits in the central nucleus of the amygdala (CeA) undergo neuroplasticity in chronic neuropathic pain resulting in increased sensory and affective pain responses. After spinal nerve ligation (SNL) injury in rats, pretreatment with a long-acting KOR antagonist, nor-binaltorphimine (nor-BNI), subcutaneously or through microinjection into the right CeA, prevented conditioned place preference (CPP) to intravenous gabapentin, suggesting that nor-BNI eliminated the aversiveness of ongoing pain. By contrast, systemic or intra-CeA administration of nor-BNI had no effect on tactile allodynia in SNL animals. Using whole-cell patch-clamp electrophysiology, we found that nor-BNI decreased synaptically evoked spiking of CeA neurons in brain slices from SNL but not sham rats. This effect was mediated through increased inhibitory postsynaptic currents, suggesting tonic disinhibition of CeA output neurons due to increased KOR activity as a possible mechanism promoting ongoing aversive aspects of neuropathic pain. Interestingly, this mechanism is not involved in SNL-induced mechanical allodynia. Kappa opioid receptor antagonists may therefore represent novel therapies for neuropathic pain by targeting aversive aspects of ongoing pain while preserving protective functions of acute pain.


Assuntos
Núcleo Central da Amígdala/metabolismo , Inibição Neural/efeitos dos fármacos , Neuralgia/prevenção & controle , Neuralgia/terapia , Receptores Opioides kappa/metabolismo , Transdução de Sinais/fisiologia , Animais , Núcleo Central da Amígdala/patologia , Dor Crônica/terapia , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Técnicas In Vitro , Masculino , Potenciais da Membrana/efeitos dos fármacos , Naltrexona/análogos & derivados , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Limiar da Dor/efeitos dos fármacos , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos
15.
J Neurophysiol ; 121(1): 96-104, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30461363

RESUMO

Osteoarthritis (OA) is a debilitating conditioning with pain as the major clinical symptom. Understanding the mechanisms that drive OA-associated chronic pain is crucial for developing the most effective analgesics. Although the degradation of the joint is the initial trigger for the development of chronic pain, the discordance between radiographic joint damage and the reported pain experience in patients, coupled with clinical features that cannot be explained by purely peripheral mechanisms, suggest there are often other factors at play. Therefore, this study considers the central contributions of chronic pain, using a monoiodoacetate (MIA) model of OA. Particularly, this study explores the functionality of descending controls over the course of the model by assessing diffuse noxious inhibitory controls (DNIC). Early-phase MIA animals have a functional DNIC system, whereas DNIC are abolished in late-phase MIA animals, indicating a dysregulation in descending modulation over the course of the model. In early-phase animals, blocking the actions of spinal α2-adrenergic receptors completely abolishes DNIC, whereas blocking the actions of spinal 5-HT7 receptors only partially decreases the magnitude of DNIC. However, activating the spinal α2-adrenergic or 5-HT7 receptors in late-phase MIA animals restored DNIC-induced neuronal inhibition. This study confirms that descending noradrenergic signaling is crucial for DNIC expression. Furthermore, we suggest a compensatory increase in descending serotonergic inhibition acting at 5-HT7 receptors as the model progresses such that receptor activation is sufficient to override the imbalance in descending controls and mediate neuronal inhibition. NEW & NOTEWORTHY This study showed that there are both noradrenergic and serotonergic components contributing to the expression of diffuse noxious inhibitory controls (DNIC). Furthermore, although a tonic descending noradrenergic tone is always crucial for the expression of DNIC, variations in descending serotonergic signaling over the course of the model mean this component plays a more vital role in states of sensitization.


Assuntos
Controle Inibitório Nociceptivo Difuso/fisiologia , Osteoartrite/metabolismo , Osteoartrite/terapia , Receptores Adrenérgicos alfa 2/metabolismo , Receptores de Serotonina/metabolismo , Medula Espinal/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Controle Inibitório Nociceptivo Difuso/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Ácido Iodoacético , Masculino , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Norepinefrina/metabolismo , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Medula Espinal/efeitos dos fármacos
16.
Biol Psychiatry ; 85(3): 214-225, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30253884

RESUMO

BACKGROUND: Autophagy has been demonstrated to play an important role in memory deficits as well as the degradation of neurotransmitter receptors. SAR405 is a newly discovered inhibitor that can specifically inhibit vacuolar sorting protein 34 and prevent autophagosome biogenesis. However, the effects of SAR405 on memory processes remain largely unknown. METHODS: Western blotting, immunofluorescence, and transmission electron microscopy were used to assess the level of autophagy after fear conditioning and SAR405 treatment. Behavioral tests, biotinylation assay, electrophysiology, and co-immunoprecipitation were used to unravel the mechanisms of SAR405 in memory consolidation. RESULTS: SAR405 infusion into the basolateral amygdala impaired long-term memory through autophagy inhibition. Furthermore, the trafficking of gamma-aminobutyric acid type A receptors (GABAARs) following fear conditioning was disrupted by SAR405, and the decreased frequency and amplitude of miniature inhibitory postsynaptic currents induced by fear conditioning were also reversed by SAR405, suggesting that SAR405 disrupted memory consolidation through blockade of the downregulated inhibitory neurotransmission in basolateral amygdala. GABAAR-associated protein (GABARAP) and its interaction with GABAAR γ2 subunit were found to be upregulated after fear conditioning, and SAR405 could suppress this increased interaction. Moreover, disruption of the GABARAP-GABAAR binding by a trans-activating transcriptional activator-GABARAP inhibitory peptide blocked the decrease in surface expression of GABAARs and attenuated long-term memory. CONCLUSIONS: The present study suggests that SAR405 can prevent the memory consolidation via intervening autophagy and GABAAR trafficking and has a potential therapeutic value for disorders characterized by exaggerated fear memories, such as posttraumatic stress disorder.


Assuntos
Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Medo/efeitos dos fármacos , Consolidação da Memória/efeitos dos fármacos , Inibição Neural/efeitos dos fármacos , Piridinas/farmacologia , Pirimidinonas/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Animais , Autofagia/efeitos dos fármacos , Medo/fisiologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Masculino , Camundongos , Microinjeções , Potenciais Pós-Sinápticos em Miniatura/fisiologia , Inibição Neural/fisiologia , Receptores de GABA-A/metabolismo , Transmissão Sináptica/fisiologia
17.
Exp Neurol ; 311: 57-66, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30257183

RESUMO

The central serotonin2B receptor (5-HT2BR) is a well-established modulator of dopamine (DA) neuron activity in the rodent brain. Recent studies in rats have shown that the effect of 5-HT2BR antagonists on accumbal and medial prefrontal cortex (mPFC) DA outflow results from a primary action in the dorsal raphe nucleus (DRN), where they activate 5-HT neurons innervating the mPFC. Although the mechanisms underlying this interaction remain largely unknown, data in the literature suggest the involvement of DRN GABAergic interneurons in the control of 5-HT activity. The present study examined this hypothesis using in vivo (intracerebral microdialysis) and in vitro (immunohistochemistry coupled to reverse transcription-polymerase chain reaction) experimental approaches in rats. Intraperitoneal (0.16 mg/kg) or intra-DRN (1 µM) administration of the selective 5-HT2BR antagonist RS 127445 increased 5-HT outflow in both the DRN and the mPFC, these effects being prevented by the intra-DRN perfusion of the GABAA antagonist bicuculline (100 µM), as well as by the subcutaneous (0.16 mg/kg) or the intra-DRN (0.1 µM) administration of the selective 5-HT1AR antagonist WAY 100635. The increase in DRN 5-HT outflow induced by the intra-DRN administration of the selective 5-HT reuptake inhibitor citalopram (0.1 µM) was potentiated by the intra-DRN administration (0.5 µM) of RS 127445 only in the absence of bicuculline perfusion. Finally, in vitro experiments revealed the presence of the 5-HT2BR mRNA on DRN GABAergic interneurons. Altogether, these results show that, in the rat DRN, 5-HT2BRs are located on GABAergic interneurons, and exert a tonic inhibitory control on 5-HT neurons innervating the mPFC.


Assuntos
Núcleo Dorsal da Rafe/metabolismo , Neurônios GABAérgicos/metabolismo , Inibição Neural/fisiologia , Receptor 5-HT2B de Serotonina/metabolismo , Neurônios Serotoninérgicos/metabolismo , Animais , Núcleo Dorsal da Rafe/efeitos dos fármacos , Antagonistas de Receptores de GABA-A/administração & dosagem , Neurônios GABAérgicos/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Inibição Neural/efeitos dos fármacos , Pirimidinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Neurônios Serotoninérgicos/efeitos dos fármacos , Serotonina/metabolismo , Antagonistas da Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/administração & dosagem , Ácido gama-Aminobutírico/metabolismo
18.
Neuropharmacology ; 148: 244-256, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30471294

RESUMO

Zinc is an abundant trace metal in the hippocampus nerve terminals. Previous studies demonstrate the ability of zinc to selectively block neurosteroid-sensitive, extrasynaptic GABA-A receptors in the hippocampus (Carver et al, 2016). Here we report that zinc prevents the seizure protective effects of the synthetic neurosteroid ganaxolone (GX) in an experimental model of epilepsy. GABA-gated and tonic currents were recorded from dissociated dentate gyrus granule cells (DGGCs), CA1 pyramidal cells (CA1PCs), and hippocampal slices from adult mice. Antiseizure effects of GX and the reversal of these effects by zinc were evaluated in fully-kindled mice expressing generalized (stage 5) seizures. In electrophysiological studies, zinc blocked the GABA-evoked and GX-potentiated GABA-gated chloride currents in DGGCs and CA1PCs in a concentration-dependent fashion similar to the competitive GABA-A receptor antagonists bicuculline and gabazine. Zinc completely blocked GX potentiation of extrasynaptic tonic currents, but not synaptic phasic currents. In hippocampus kindling studies, systemic administration of GX produced a dose-dependent suppression of behavioral and electrographic seizures in fully-kindled mice with complete seizure protection at the 10 mg/kg dose. However, the antiseizure effects of GX were significantly prevented by intrahippocampal administration of zinc (ED50, 150 µM). The zinc antagonistic response was reversible as animals responded normally to GX administration 24 h post-zinc blockade. These results demonstrate that zinc reduces the antiseizure effects of GX by selectively blocking extrasynaptic δGABA-A receptors in the hippocampus. These pharmacodynamic interactions have clinical implications in neurosteroid therapy for brain conditions associated with zinc fluctuations.


Assuntos
Hipocampo/efeitos dos fármacos , Neuroesteroides/farmacologia , Pregnanolona/análogos & derivados , Convulsões/prevenção & controle , Zinco/farmacologia , Animais , Bicuculina/farmacologia , Relação Dose-Resposta a Droga , Antagonistas de Receptores de GABA-A/farmacologia , Hipocampo/fisiologia , Excitação Neurológica/efeitos dos fármacos , Masculino , Camundongos , Microinjeções , Inibição Neural/efeitos dos fármacos , Pregnanolona/antagonistas & inibidores , Pregnanolona/farmacologia , Piridazinas/farmacologia , Receptores de GABA-A/fisiologia , Zinco/administração & dosagem
19.
Neurosci Lett ; 694: 148-153, 2019 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-30500395

RESUMO

Although gabapentin (GBP) is a first-line treatment in the management of neuropathic pain, its mechanism of action is incompletely understood. We have previously shown, in rats made neuropathic following sciatic chronic constriction injury, that IP injection of 100 mg/kg GBP decreases overall excitability of spinal cord slices obtained ex vivo. Excitability was assessed using confocal imaging to monitor the amplitude of K+- induced increases in cytoplasmic Ca2+. This decrease in excitability involved a reduction in the frequency and amplitude of spontaneous EPSC's (sEPSC) in putative excitatory substantia gelatinosa neurons and an increase in sEPSC frequency in putative inhibitory neurons. We used have whole-cell recording to compare these ex vivo actions of GBP with its acute in vitro effects on spinal cord slices obtained from neuropathic but drug-free rats. While GBP (100µM) decreased sEPSC amplitude and frequency in excitatory neurons in vitro in a similar fashion to effects observed ex vivo, sEPSC frequency in inhibitory neurons was decreased in vitro rather than increased. Acute in vitro application of GBP also failed to decrease the overall excitability of slices from neuropathic animals as monitored by confocal Ca2+ imaging. Since spinal cord slices in vitro are disconnected from the periphery and higher brain centres, the GBP-induced increase in sEPSC frequency in inhibitory neurons previously reported and seen ex vivo must result from extra-spinal actions. It may be attributable to alterations in descending neurotrophic control of dorsal horn circuitry.


Assuntos
Analgésicos/administração & dosagem , Gabapentina/administração & dosagem , Neuralgia/fisiopatologia , Substância Gelatinosa/efeitos dos fármacos , Substância Gelatinosa/fisiologia , Animais , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Hiperalgesia/fisiopatologia , Masculino , Inibição Neural/efeitos dos fármacos , Ratos Sprague-Dawley
20.
Neuroscience ; 397: 1-11, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30500613

RESUMO

The inspiratory motor activities are greater in the intercostal muscles positioned at more rostral thoracic segments. This rostro-caudal gradient of the thoracic inspiratory motor activity is thought to be generated by the spinal interneurons. To clarify the involvement of the inhibitory thoracic interneurons in this rostro-caudal gradient, we examined the effects of 10 µM strychnine, an antagonist of glycine and GABAA receptors, applied to the neonatal rat thoracic spinal cord. The respiratory-related interneuron activities were optically recorded from thoracic segments in the isolated neonatal rat brainstem-spinal cord preparations stained with voltage-sensitive dye, and the electrical inspiratory motor activities were obtained from the third and eleventh thoracic ventral roots (T3VR, T11VR). Although strychnine caused seizure-like activities in all of the ventral roots recorded, the inspiratory motor activities continued. The inspiratory optical signals in the rostral thoracic segments (T2-T5) were significantly larger than those in the caudal thoracic segments (T9-T11) regardless of the existence of strychnine. Similarly, the percent ratio of the amplitude of the inspiratory electrical activity in the T3VR under control and strychnine was significantly larger than that in the T11VR regardless of the existence of strychnine. Strychnine significantly increased the inspiratory activity in both the T3VR and T11VR. These results suggest that the glycinergic and GABAergic inhibitory interneurons are not essential to generate the rostro-caudal gradient in the neonatal rat thoracic inspiratory motor outputs, but these interneurons are likely to play a role in the inhibitory control of inspiratory motor output.


Assuntos
Inalação/fisiologia , Interneurônios/fisiologia , Movimento/fisiologia , Inibição Neural/fisiologia , Músculos Respiratórios/fisiologia , Raízes Nervosas Espinhais/fisiologia , Animais , Animais Recém-Nascidos , Tronco Encefálico/efeitos dos fármacos , Tronco Encefálico/fisiologia , Glicina/metabolismo , Inalação/efeitos dos fármacos , Interneurônios/efeitos dos fármacos , Movimento/efeitos dos fármacos , Inibição Neural/efeitos dos fármacos , Neurotransmissores/farmacologia , Ratos Wistar , Receptores de GABA-A/metabolismo , Receptores da Glicina/antagonistas & inibidores , Receptores da Glicina/metabolismo , Músculos Respiratórios/efeitos dos fármacos , Músculos Respiratórios/inervação , Convulsões/fisiopatologia , Raízes Nervosas Espinhais/efeitos dos fármacos , Estricnina/farmacologia , Vértebras Torácicas , Técnicas de Cultura de Tecidos , Imagens com Corantes Sensíveis à Voltagem , Ácido gama-Aminobutírico/metabolismo
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