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1.
BMC Neurol ; 19(1): 237, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615444

RESUMO

BACKGROUND: The anterior cingulate cortex (ACC) is a key structure of the pain processing network. Several structural and functional alterations of this brain area have been found in migraine. In addition, altered serotonergic neurotransmission has been repeatedly implicated in the pathophysiology of migraine, although the exact mechanism is not known. Thus, our aim was to investigate the relationship between acute increase of brain serotonin (5-HT) level and the activation changes of the ACC using pharmacological challenge MRI (phMRI) in migraine patients and healthy controls. METHODS: Twenty-seven pain-free healthy controls and six migraine without aura patients participated in the study. All participant attended to two phMRI sessions during which intravenous citalopram, a selective serotonin reuptake inhibitor (SSRI), or placebo (normal saline) was administered. We used region of interest analysis of ACC to compere the citalopram evoked activation changes of this area between patients and healthy participants. RESULTS: Significant difference in ACC activation was found between control and patient groups in the right pregenual ACC (pgACC) during and after citalopram infusion compared to placebo. The extracted time-series showed that pgACC activation increased in migraine patients compared to controls, especially in the first 8-10 min of citalopram infusion. CONCLUSIONS: Our results demonstrate that a small increase in 5-HT levels can lead to increased phMRI signal in the pregenual part of the ACC that is involved in processing emotional aspects of pain. This increased sensitivity of the pgACC to increased 5-HT in migraine may contribute to recurring headache attacks and increased stress-sensitivity in migraine.


Assuntos
Giro do Cíngulo/metabolismo , Giro do Cíngulo/fisiopatologia , Transtornos de Enxaqueca/metabolismo , Transtornos de Enxaqueca/fisiopatologia , Serotonina/metabolismo , Adulto , Mapeamento Encefálico/métodos , Citalopram/farmacologia , Método Duplo-Cego , Feminino , Giro do Cíngulo/efeitos dos fármacos , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Inibidores de Captação de Serotonina/farmacologia
2.
J Neuroinflammation ; 16(1): 132, 2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31255170

RESUMO

BACKGROUND: Liver X receptors (LXRs), including LXRα and LXRß, are key regulators of transcriptional programs for both cholesterol homeostasis and inflammation in the brain. Here, the modes of action of LXRs and the epigenetic mechanisms regulating LXRß expression in anterior cingulate cortex (ACC) of chronic inflammatory pain (CIP) are investigated. METHODS: The deficit of LXR isoform and analgesic effect of LXR activation by GW3965 were evaluated using the mouse model of CIP induced by hindpaw injection of complete Freund's adjuvant (CFA). The mechanisms involved in GW-mediated analgesic effects were analyzed with immunohistochemical methods, ELISA, co-immunoprecipitation (Co-IP), Western blot, and electrophysiological recording. The epigenetic regulation of LXRß expression was investigated by chromatin immunoprecipitation, quantitative real-time PCR, and sequencing. RESULTS: We revealed that CFA insult led to LXRß reduction in ACC, which was associated with upregulated expression of histone deacetylase 5 (HDAC5), and knockdown of LXRß by shRNA led to thermal hyperalgesia. Co-IP showed that LXRß interacted with NF-κB p65 physically. LXRß activation by GW3965 exerted analgesic effects by inhibiting the nuclear translocation of NF-κB, reducing the phosphorylation of mitogen-activated protein kinases (MAPKs) in ACC, and decreasing the promoted input-output and enhanced mEPSC frequency in ACC neurons after CFA exposure. In vitro experiments confirmed that HDAC5 triggered histone deacetylation on the promoter region of Lxrß, resulting in downregulation of Lxrß transcription. CONCLUSION: These findings highlight an epigenetic mechanism underlying LXRß deficits linked to CIP, and LXRß activation may represent a potential novel target for the treatment of CIP with an alteration in inflammation responses and synaptic transmission in ACC.


Assuntos
Dor Crônica/metabolismo , Epigênese Genética/fisiologia , Adjuvante de Freund/toxicidade , Giro do Cíngulo/metabolismo , Histona Desacetilases/biossíntese , Receptores X do Fígado/metabolismo , Animais , Sequência de Bases , Dor Crônica/induzido quimicamente , Dor Crônica/genética , Epigênese Genética/efeitos dos fármacos , Giro do Cíngulo/efeitos dos fármacos , Histona Desacetilases/genética , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Receptores X do Fígado/antagonistas & inibidores , Receptores X do Fígado/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL
3.
Psychopharmacology (Berl) ; 236(8): 2325-2336, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31201476

RESUMO

RATIONALE: Patients with obsessive-compulsive disorder (OCD) have been found to show exaggerated error responses and prediction error learning signals in a variety of EEG and fMRI tasks, with data converging on the anterior cingulate cortex as a key locus of dysfunction. Considerable evidence has linked prediction error processing to dopaminergic function. OBJECTIVE: In this study, we investigate potential dopaminergic dysfunction during reward processing in the context of OCD. METHODS: We studied OCD patients (n = 18) and controls (n = 18) whilst they learned probabilistic associations between abstract stimuli and monetary rewards in the fMRI scanner involving administration (on separate visits) of a dopamine receptor agonist, pramipexole 0.5 mg; a dopamine receptor antagonist, amisulpride 400 mg; and placebo. We fitted a Q-learning computational model to fMRI prediction error responses; group differences were examined in anterior cingulate and nucleus accumbens regions of interest. RESULTS: There were no significant group, drug, or interaction effects in the number of correct choices; computational modeling suggested a marginally significant difference in learning rates between groups (p = 0.089, partial ƞ2 = 0.1). In the imaging results, there was a significant interaction of group by drug (p = 0.013, partial ƞ2 = 0.13). OCD patients showed abnormally strong cingulate signaling of prediction errors during omission of an expected reward, with unexpected reduction by both pramipexole and amisulpride (p = 0.014, partial ƞ2 = 0.26, 1-ß error probability = 0.94). Exaggerated cingulate prediction error signaling to omitted reward in placebo was related to trait subjective difficulty in self-regulating behavior in OCD. CONCLUSIONS: Our data support cingulate dysfunction during reward processing in OCD, and bidirectional remediation by dopaminergic modulation, suggesting that exaggerated cingulate error signals in OCD may be of dopaminergic origin. The results help to illuminate the mechanisms through which dopamine receptor antagonists achieve therapeutic benefit in OCD. Further research is needed to disentangle the different functions of dopamine receptor agonists and antagonists during bidirectional modulation of cingulate activation.


Assuntos
Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/diagnóstico por imagem , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Recompensa , Adulto , Dopamina/metabolismo , Método Duplo-Cego , Feminino , Previsões , Giro do Cíngulo/metabolismo , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Núcleo Accumbens/diagnóstico por imagem , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Transtorno Obsessivo-Compulsivo/metabolismo , Estimulação Luminosa/métodos
4.
Elife ; 82019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31099753

RESUMO

The medial thalamus (MThal), anterior cingulate cortex (ACC) and striatum play important roles in affective-motivational pain processing and reward learning. Opioids affect both pain and reward through uncharacterized modulation of this circuitry. This study examined opioid actions on glutamate transmission between these brain regions in mouse. Mu-opioid receptor (MOR) agonists potently inhibited MThal inputs without affecting ACC inputs to individual striatal medium spiny neurons (MSNs). MOR activation also inhibited MThal inputs to the pyramidal neurons in the ACC. In contrast, delta-opioid receptor (DOR) agonists disinhibited ACC pyramidal neuron responses to MThal inputs by suppressing local feed-forward GABA signaling from parvalbumin-positive interneurons. As a result, DOR activation in the ACC facilitated poly-synaptic (thalamo-cortico-striatal) excitation of MSNs by MThal inputs. These results suggest that opioid effects on pain and reward may be shaped by the relative selectivity of opioid drugs to the specific circuit components.


Assuntos
Analgésicos Opioides/metabolismo , Corpo Estriado/efeitos dos fármacos , Giro do Cíngulo/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Tálamo/efeitos dos fármacos , Animais , Aprendizagem/efeitos dos fármacos , Camundongos , Dor , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas
5.
Neurobiol Learn Mem ; 161: 92-105, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30946882

RESUMO

Cocaine use disorder (CUD) is associated with prefrontal cortex dysfunction and cognitive deficits that may contribute to persistent relapse susceptibility. As the relationship between cognitive deficits, cortical abnormalities and drug seeking is poorly understood, development of relevant animal models is of high clinical importance. Here, we used an animal model to characterize working memory and reversal learning in rats with a history of extended access cocaine self-administration and prolonged abstinence. We also investigated immediate and long-term functional changes within the prelimbic cortex (PrL) in relation to cognitive performance and drug-seeking. Adult male rats underwent 6 days of short-access (1 h/day) followed by 12 days of long-access (6 h/day) cocaine self-administration, or received passive saline infusions. Next, rats were tested in delayed match-to-sample (DMS) and (non)match-to-sample (NMS) tasks, and finally in a single context + cue relapse test on day 90 of abstinence. We found that a history of chronic cocaine self-administration impaired working memory, though sparing reversal learning, and that the components of these cognitive measures correlated with later drug-seeking. Further, we found that dysregulated metabolic activity and mGlu5 receptor signaling in the PrL of cocaine rats correlated with past working memory performance and/or drug-seeking, as indicated by the analysis of cytochrome oxidase reactivity, mGlu5 and Homer 1b/c protein expression, as well as Arc mRNA expression in mGlu5-positive cells. These findings advocate for a persistent post-cocaine PrL dysfunction, rooted in ineffective compensatory changes and manifested as impaired working memory performance and hyperreactivity to cocaine cues. Considering the possible interplay between the neural correlates underlying post-cocaine cognitive deficits and drug-seeking, cognitive function should be evaluated and considered when developing neurobiologically-based treatments of cocaine relapse.


Assuntos
Transtornos Relacionados ao Uso de Cocaína , Cocaína/farmacologia , Disfunção Cognitiva , Inibidores da Captação de Dopamina/farmacologia , Giro do Cíngulo , Memória de Curto Prazo , Córtex Pré-Frontal , Receptor de Glutamato Metabotrópico 5/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Transtornos Relacionados ao Uso de Cocaína/complicações , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/metabolismo , Giro do Cíngulo/fisiopatologia , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Memória de Curto Prazo/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Ratos , Ratos Sprague-Dawley , Autoadministração
6.
Psychiatry Res ; 275: 78-85, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30884334

RESUMO

Findings from in vivo brain proton magnetic resonance spectroscopy (1H MRS) and preclinical studies have suggested region- and medication status-dependent increases in glutamate (Glu) levels and deficiencies in glutathione (GSH) levels in schizophrenia. N-acetylcysteine (NAC), a GSH synthesis precursor, has demonstrated modest clinical benefit in schizophrenia. The objective of this study was to examine the effects of acute administration of NAC on GSH and Glu levels measured with 1H MRS in 19 patients with schizophrenia and 20 healthy control subjects. Levels of GSH were acquired in dorsal anterior cingulate cortex (dACC), and those of Glu in dACC and medial prefrontal cortex (mPFC), at baseline and 60 min following acute oral administration of 2400 mg of NAC. No differences in the levels of GSH or Glu were found at baseline or following NAC administration between patients with schizophrenia and control subjects in either of the targeted brain regions. Future studies measuring GSH levels in brain regions previously found to exhibit glutamatergic abnormalities or using genetic polymorphisms, while controlling for the age and medication status of the cohorts, are warranted to better identify groups of patients more likely to respond to NAC and its mode of action and mechanisms.


Assuntos
Acetilcisteína/farmacologia , Depuradores de Radicais Livres/farmacologia , Ácido Glutâmico/metabolismo , Glutationa/metabolismo , Giro do Cíngulo/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Acetilcisteína/administração & dosagem , Adolescente , Adulto , Feminino , Depuradores de Radicais Livres/administração & dosagem , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Esquizofrenia/metabolismo , Adulto Jovem
7.
Psychopharmacology (Berl) ; 236(7): 1985-1997, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30820633

RESUMO

RATIONALE: Anterior cingulate cortex (ACC) glutamatergic abnormalities are reported in treatment-resistant schizophrenia (TRS) and implicated in functional dysconnectivity and psychopathology. Preclinical evidence indicates riluzole reduces synaptic glutamate. However, it is unknown whether riluzole can modulate glutamate metabolite levels and associated functional connectivity in TRS. OBJECTIVES: To examine the relationship between glutamatergic function and cortical connectivity and determine if riluzole can modulate glutamate metabolite levels and cortical functional connectivity in TRS. METHODS: Nineteen TRS patients and 18 healthy volunteers (HV) underwent magnetic resonance imaging consisting of MR spectroscopy measuring ACC glutamate plus glutamine (Glx), fMRI measuring resting ACC-functional connectivity, and arterial spin labelling measuring regional cerebral blood flow (rCBF), and clinical measures. They then received 50 mg riluzole twice daily for 2 days when imaging was repeated. RESULTS: Baseline (pre-riluzole) Glx levels were correlated directly with negative symptom severity (r = 0.49; p = 0.03) and inversely with verbal learning in TRS (r = - 0.63; p = 0.002), but not HV (r = - 0.24; p = 0.41). Connectivity between the ACC and anterior prefrontal cortex (aPFC) was correlated with verbal learning in TRS (r = 0.49; p = 0.04), but not HV (r = 0.28; p = 0.33). There was a significant group × time interaction effect on Glx levels (p < 0.05) and on ACC connectivity to the aPFC (p < 0.05, FWE-corrected). Riluzole decreased Glx and increased ACC-aPFC connectivity in TRS relative to HV. Change in Glx correlated inversely with change in ACC-aPFC connectivity in TRS (r = - 0.52; p = 0.02) but not HV (r = 0.01; p = 0.98). Riluzole did not alter rCBF (p > 0.05), indicating absence of a non-specific blood flow effect. CONCLUSION: Results indicate glutamatergic function and cortical connectivity are linked to symptoms and cognitive measures and that it is possible to pharmacologically modulate them in TRS.


Assuntos
Ácido Glutâmico/metabolismo , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Riluzol/uso terapêutico , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Psicologia do Esquizofrênico , Adulto , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Feminino , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/metabolismo , Humanos , Imagem por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Riluzol/farmacologia , Esquizofrenia/diagnóstico por imagem , Resultado do Tratamento , Adulto Jovem
8.
Georgian Med News ; (286): 116-122, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30829602

RESUMO

Anterior cingulate cortex (ACC), which is activated by noxious stimuli, is involved in pain processing, the neural mechanisms of the ACC involvement in affective pain have yet to be elaborated. To study relation antinociceptive effects induced by non-steroidal anti-inflammatory drugs (NSAIDs) with endogenous opioid system we treated experimental rats with opioid receptor antagonists, naloxone and CTOP in the ACC pre- and post-following microinjections with NSAIDs. We measured nociceptive thermal paw withdrawal latencies and mechanical thresholds in rats' formalin test following microinjections of NSAIDs (diclofenac, ketoprofen, ketorolac and lornoxicam), saline or opioid receptor antagonists, naloxone and CTOP in the ACC. Five minutes following intraplantar formalin injection all animals showed a significant reduction in thermal paw withdrawal latency and mechanical withdrawal threshold compared to pre-baseline values. Fifteen minutes after formalin injection, diclofenac, ketoprofen, ketorolac and lornoxicam clearly showed antinociceptive effects of NSAIDs. When pretreated with naloxone and CTOP we found a significant reduction of analgesic effects of NSAIDs as well as post-treatment of these completely abolished NSAIDs-induced antinociception. We demonstrated that microinjection widely used non-opioid, NSAID analgesics, diclofenac, ketoprofen, ketorolac and lornoxicam injected into the rostral part of the ACC, induced antinociception in rats. The present findings support the concept that NSAIDs-evoked antinociception is mediated via descending endogenous opioid system.


Assuntos
Anti-Inflamatórios não Esteroides , Giro do Cíngulo , Naloxona , Somatostatina/análogos & derivados , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Giro do Cíngulo/efeitos dos fármacos , Cetorolaco/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes , Percepção da Dor , Ratos , Ratos Wistar , Somatostatina/farmacologia
9.
Mol Pain ; 15: 1744806919842958, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30900509

RESUMO

Matrix metalloproteinases (MMPs) have been suggested to contribute to long-term potentiation, behavioral learning, and memory. In the dorsal horn of spinal cord, MMPs were reported to contribute to injury-related changes, and inhibitors of MMPs have been proposed as potential analgesics. However, it is unclear whether MMP inhibitors produce these effects by inhibiting the function of N-methyl-D-aspartate receptor (NMDAR), a key receptor for the induction of long-term potentiation. In this study, we wanted to examine if MMP inhibitors affect NMDAR-mediated excitatory postsynaptic currents in the anterior cingulate cortex of adult mice. Among different subtype inhibitors we used, we found that MMP-9 and MMP-2/9 inhibitors did not change NMDAR-mediated excitatory postsynaptic currents. However, MMP-3 and broad-spectrum MMP inhibitors reduced the NMDAR-mediated excitatory postsynaptic currents. Consistently, MMP-9 and MMP-2/9 inhibitors had no effect on NMDAR-dependent long-term potentiation, but MMP-3 and broad-spectrum MMP inhibitors inhibited the induction of long-term potentiation. Our results suggest that MMP inhibitors may produce their effects by inhibiting NMDAR functions in central synapses.


Assuntos
Giro do Cíngulo/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Inibidores de Metaloproteinases de Matriz/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Giro do Cíngulo/efeitos dos fármacos , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
10.
Transl Psychiatry ; 9(1): 64, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718459

RESUMO

Due to lacking predictors of depression recovery, successful treatment of major depressive disorder (MDD) is frequently only achieved after therapeutic optimization leading to a prolonged suffering of patients. This study aimed to determine neural prognostic predictors identifying non-remitters prior or early after treatment initiation. Moreover, it intended to detect time-sensitive neural mediators indicating depression recovery. This longitudinal, interventional, single-arm, open-label, phase IV, pharmacological functional magnetic resonance imaging (fMRI) study comprised four scans at important stages prior (day 0) and after escitalopram treatment initiation (day 1, 28, and 56). Totally, 22 treatment-free MDD patients (age mean ± SD: 31.5 ± 7.7; females: 50%) suffering from a concurrent major depressive episode without any comorbid DSM-IV axis I diagnosis completed the study protocol. Primary outcome were neural prognostic predictors of depression recovery. Enhanced de-activation of anterior medial prefrontal cortex (amPFC, single neural mediator) indicated depression recovery correlating with MADRS score and working memory improvements. Strong dorsolateral PFC (dlPFC) activation and weak dlPFC-amPFC, dlPFC-posterior cingulate cortex (PCC), dlPFC-parietal lobe (PL) coupling (three prognostic predictors) hinted at depression recovery at day 0 and 1. Preresponse prediction of continuous (dlPFC-PL: R2day1 = 55.9%, 95% CI: 22.6-79%, P < 0.005) and dichotomous (specificity/sensitivity: SP/SNday1 = 0.91/0.82) recovery definitions remained significant after leave-one-out cross-validation. Identified prefrontal neural predictors might propel the future development of fMRI markers for clinical decision making, which could lead to increased response rates and adherence during acute phase treatment periods. Moreover, this study underscores the importance of the amPFC in depression recovery.


Assuntos
Citalopram/farmacologia , Conectoma/normas , Transtorno Depressivo Maior , Memória de Curto Prazo , Rede Nervosa , Córtex Pré-Frontal , Inibidores de Captação de Serotonina/farmacologia , Adulto , Conectoma/métodos , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Feminino , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/fisiopatologia , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Memória de Curto Prazo/fisiologia , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiopatologia , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/efeitos dos fármacos , Lobo Parietal/fisiopatologia , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Prognóstico , Sensibilidade e Especificidade , Adulto Jovem
11.
Mol Pain ; 15: 1744806919832718, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30717631

RESUMO

The neuropeptide of calcitonin gene-related peptide (CGRP) plays critical roles in chronic pain, especially in migraine. Immunohistochemistry and in situ hybridization studies have shown that CGRP and its receptors are expressed in cortical areas including pain perception-related prefrontal anterior cingulate cortex. However, less information is available for the functional roles of CGRP in cortical regions such as the anterior cingulate cortex (ACC). Recent studies have consistently demonstrated that long-term potentiation is a key cellular mechanism for chronic pain in the ACC. In the present study, we used 64-electrode array field recording system to investigate the effect of CGRP on excitatory transmission in the ACC. We found that CGRP induced potentiation of synaptic transmission in a dose-dependently manner (1, 10, 50, and 100 nM). CGRP also recruited inactive circuit in the ACC. An application of the calcitonin receptor-like receptor antagonist CGRP8-37 blocked CGRP-induced chemical long-term potentiation and the recruitment of inactive channels. CGRP-induced long-term potentiation was also blocked by N-methyl-D-aspartate (NMDA) receptor antagonist AP-5. Consistently, the application of CGRP increased NMDA receptor-mediated excitatory postsynaptic currents. Finally, we found that CGRP-induced long-term potentiation required the activation of calcium-stimulated adenylyl cyclase subtype 1 (AC1) and protein kinase A. Genetic deletion of AC1 using AC1-/- mice, an AC1 inhibitor NB001 or a protein kinase A inhibitor KT5720, all reduced or blocked CGRP-induced potentiation. Our results provide direct evidence that CGRP may contribute to synaptic potentiation in important physiological and pathological conditions in the ACC, an AC1 inhibitor NB001 may be beneficial for the treatment of chronic headache.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Giro do Cíngulo/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , 2-Amino-5-fosfonovalerato/farmacologia , Adenilil Ciclases/deficiência , Adenilil Ciclases/genética , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Carbazóis/farmacologia , Estimulação Elétrica , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Giro do Cíngulo/metabolismo , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Patch-Clamp , Pirróis/farmacologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Transdução de Sinais/efeitos dos fármacos
12.
Neuroimage Clin ; 21: 101652, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30639181

RESUMO

BACKGROUND: Cocaine use has been consistently associated with decreased gray matter volumes in the prefrontal cortex. However, it is unclear if such neuroanatomical abnormalities depict either pre-existing vulnerability markers or drug-induced consequences. Thus, this longitudinal MRI study investigated neuroplasticity and cognitive changes in relation to altered cocaine intake. METHODS: Surface-based morphometry, cocaine hair concentration, and cognitive performance were measured in 29 cocaine users (CU) and 38 matched controls at baseline and follow-up. Based on changes in hair cocaine concentration, CU were classified either as Decreasers (n = 15) or Sustained Users (n = 14). Surface-based morphometry measures did not include regional tissue volumes. RESULTS: At baseline, CU displayed reduced cortical thickness (CT) in lateral frontal regions, and smaller cortical surface area (CSA) in the anterior cingulate cortex, compared to controls. In Decreasers, CT of the lateral frontal cortex increased whereas CT within the same regions tended to further decrease in Sustained Users. In contrast, no changes were found for CSA and subcortical structures. Changes in CT were linked to cognitive performance changes and amount of cocaine consumed over the study period. CONCLUSIONS: These results suggest that frontal abnormalities in CU are partially drug-induced and can recover with decreased substance use. Moreover, recovery of frontal CT is accompanied by improved cognitive performance confirming that cognitive decline associated with cocaine use is potentially reversible.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/patologia , Cocaína/efeitos adversos , Cognição/efeitos dos fármacos , Lobo Frontal/patologia , Adulto , Atenção/efeitos dos fármacos , Cocaína/administração & dosagem , Transtornos Relacionados ao Uso de Cocaína/psicologia , Disfunção Cognitiva/complicações , Disfunção Cognitiva/psicologia , Feminino , Lobo Frontal/efeitos dos fármacos , Substância Cinzenta/efeitos dos fármacos , Substância Cinzenta/patologia , Giro do Cíngulo/efeitos dos fármacos , Humanos , Estudos Longitudinais , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/patologia
13.
Int J Neuropsychopharmacol ; 22(4): 317-328, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668714

RESUMO

BACKGROUND: Pathological anxiety originates from a complex interplay of genetic predisposition and environmental factors, acting via epigenetic mechanisms. Epigenetic processes that can counteract detrimental genetic risk towards innate high anxiety are not well characterized. METHODS: We used female mouse lines of selectively bred high (HAB)- vs low (LAB)-innate anxiety-related behavior and performed select environmental and pharmacological manipulations to alter anxiety levels as well as brain-specific manipulations and immunohistochemistry to investigate neuronal mechanisms associated with alterations in anxiety-related behavior. RESULTS: Inborn hyperanxiety of high anxiety-like phenotypes was effectively reduced by environmental enrichment exposure. c-Fos mapping revealed that hyperanxiety in high anxiety-like phenotypes was associated with blunted challenge-induced neuronal activation in the cingulate-cortex, which was normalized by environmental enrichment. Relating this finding with epigenetic modifications, we found that high anxiety-like phenotypes (compared with low-innate anxiety phenotypes) showed reduced acetylation in the hypoactivated cingulate-cortex neurons following a mild emotional challenge, which again was normalized by environmental enrichment. Paralleling the findings using environmental enrichment, systemic administration of histone-deacetylase-inhibitor MS-275 elicited an anxiolytic-like effect, which was correlated with increased acetylated-histone-3 levels within cingulate-cortex. Finally, as a proof-of-principle, local MS-275 injection into cingulate-cortex rescued enhanced innate anxiety and increased acetylated-histone-3 within the cingulate-cortex, suggesting this epigenetic mark as a biomarker for treatment success. CONCLUSIONS: Taken together, the present findings provide the first causal evidence that the attenuation of high innate anxiety-like behavior via environmental/pharmacological manipulations is epigenetically mediated via acetylation changes within the cingulate-cortex. Finally, histone-3 specific histone-deacetylase-inhibitor could be of therapeutic importance in anxiety disorders.


Assuntos
Ansiolíticos/farmacologia , Ansiedade , Comportamento Animal , Meio Ambiente , Epigênese Genética , Giro do Cíngulo , Inibidores de Histona Desacetilases/farmacologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Ansiedade/reabilitação , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Benzamidas/farmacologia , Feminino , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/metabolismo , Giro do Cíngulo/fisiopatologia , Histonas/efeitos dos fármacos , Histonas/metabolismo , Instinto , Masculino , Camundongos , Camundongos Endogâmicos , Estudo de Prova de Conceito , Piridinas/farmacologia
14.
Transl Psychiatry ; 9(1): 30, 2019 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-30664639

RESUMO

Depression in adolescence is frequently characterised by symptoms of irritability. Fluoxetine is the antidepressant with the most favourable benefit:risk ratio profile to treat adolescent depression, but the neural mechanisms underlying antidepressant drugs in the young brain are still poorly understood. Previous studies have characterised the neural effects of long-term fluoxetine treatment in depressed adolescents, but these are limited by concurrent mood changes and a lack of placebo control. There is also recent evidence suggesting that fluoxetine reduces the processing of anger in young healthy volunteers, which is consistent with its effect for the treatment of irritability in this age group, but this remains to be investigated in depressed adolescents. Here we assessed the effects of a single, first dose of 10 mg fluoxetine vs. placebo on neural response to anger cues using fMRI in a sample of adolescents with Major Depressive Disorder (MDD) who had been recently prescribed fluoxetine. As predicted, adolescents receiving fluoxetine showed reduced activity in response to angry facial expressions in the amygdala-hippocampal region relative to placebo. Activity in the dorsal anterior cingulate cortex (dACC) was also increased. No changes in symptoms were observed. These results demonstrate, for the first time in depressed adolescents, that fluoxetine has immediate neural effects on core components of the cortico-limbic circuitry prior to clinical changes in mood. The effect on anger is consistent with our previous work and could represent a key mechanism through which fluoxetine may act to alleviate irritability symptoms in adolescent depression.


Assuntos
Ira/efeitos dos fármacos , Transtorno Depressivo Maior/tratamento farmacológico , Fluoxetina/administração & dosagem , Inibidores de Captação de Serotonina/administração & dosagem , Adolescente , Tonsila do Cerebelo/efeitos dos fármacos , Mapeamento Encefálico , Expressão Facial , Feminino , Giro do Cíngulo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Humanos , Imagem por Ressonância Magnética , Masculino
15.
Behav Brain Res ; 362: 21-27, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30630018

RESUMO

Alcohol consumption has been identified as a causal factor promoting changes in different molecular and cellular mechanisms resulting in neurodegeneration. This process is specific to certain brain regions and its effects on different areas of the brain can result in a variety of deleterious consequences. The prefrontal cortex (PFC) appears to be particularly sensitive to alcohol-induced neurodegeneration; this region is quite complex, as it is responsible for high order mental processes such as decision making. Thus, it is important to have precise and unbiased data of neuronal morphology parameters to understand the real effects of alcohol on the PFC. This study aimed to investigate alcohol-induced neurodegeneration in the PFC by utilizing behavioral and stereological methods. In the first phase of the study, we utilized eighteen animals, six controls and twelve alcohol-treated, that were submitted to voluntary chronic alcohol ingestion for four or eight weeks. Their brains were analyzed by design-based stereology methods to assess number and volume parameters regarding neuronal integrity in regions of the PFC (prelimbic - PL, infralimbic - IL and anterior cingulate - ACC). In the second phase of the study, six animals were utilized as controls and eight animals were submitted to the same alcohol ingestion protocol and to a behavioral decision-making test. In conclusion, our findings indicate that chronic alcohol consumption promotes a decrease in volume in the prelimbic and in the anterior cingulate, a decrease of mean neuronal volume in the anterior cingulate cortex and a decrease of total volume of neurons in the IL area. We did not observe changes in decision-making behavior in either of the two periods of alcohol intake. This shows that morphological changes occur in specific regions of the prefrontal cortex, a noble area of cognitive functions, induced by chronic alcohol consumption.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Etanol/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Animais , Cognição/efeitos dos fármacos , Tomada de Decisões/efeitos dos fármacos , Giro do Cíngulo/efeitos dos fármacos , Masculino , Neurônios/efeitos dos fármacos , Ratos Wistar
16.
Psychoneuroendocrinology ; 99: 154-165, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30245328

RESUMO

Short- and long-term treatment with glucocorticoids is widely used in clinical practice and frequently induces features of iatrogenic Cushing syndrome, such as abdominally centered weight gain. Despite decades of glucocorticoids usage, the mechanisms underlying these side effects are still only partly understood. One possibility is that glucocorticoids impact subcortical (hypothalamus, amygdala, insula) and cortical (orbitofrontal and cingulate cortex) brain regions involved in appetite regulation and reward processing. In the present study, we used functional magnetic resonance imaging (fMRI) to study the acute effects of a prednisolone infusion on reactivity of brain reward systems to food stimuli. Twenty healthy normal-weight men were tested in a randomized, double-blind, cross-over study. After an overnight fast and infusion of either 250 mg prednisolone or placebo (always administered between 8 and 9 A M), fMRI scans were taken while presenting food and object pictures in a Go/NoGo (GNG) task. At home, participants were asked to register what they had eaten. On the following morning they came back to the lab and had a supervised ad libitum breakfast at a standardized buffet. Food-Go in contrast to Object-Go pictures yielded increased blood oxygen level dependent (BOLD) activity in hippocampus, amygdala, orbitofrontal cortex, insula and anterior cingulate cortex. Prednisolone increased activation in the bilateral amygdala and right insula for approach-associated food pictures. The buffet test did not reveal significant differences in calorie consumption or preferences of different macronutrients. However, prednisolone-induced insula reactivity to Food-Go images was associated with greater caloric intake, both at home and in the standardized buffet. In sum, we observed a specific effect of prednisolone on the BOLD response of the amygdala and insula to approach-associated food stimuli. As these brain areas have previously been implicated in hedonic eating, the present pattern of results may reflect an increased anticipated reward value of food modulated by glucocorticoids. These effects might potentially drive increased food intake and weight gain under prolonged glucocorticoid treatment.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Prednisolona/farmacologia , Corticosteroides , Adulto , Tonsila do Cerebelo/metabolismo , Encéfalo/efeitos dos fármacos , Córtex Cerebral/metabolismo , Estudos Cross-Over , Método Duplo-Cego , Ingestão de Alimentos , Ingestão de Energia , Comportamento Alimentar/fisiologia , Alimentos , Preferências Alimentares/fisiologia , Glucocorticoides/farmacologia , Giro do Cíngulo/efeitos dos fármacos , Voluntários Saudáveis , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Filosofia , Estimulação Luminosa , Prednisolona/metabolismo , Córtex Pré-Frontal , Recompensa , Adulto Jovem
17.
Mol Neurobiol ; 56(4): 2482-2494, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30032425

RESUMO

The anterior cingulate cortex (ACC) is a well-known brain area that is associated with pain perception. Previous studies reported that the ACC has a specific role in the emotional processing of pain. Chronic pain is characterized by long-term potentiation that is induced in pain pathways and contributes to hyperalgesia caused by peripheral nerve injury. The mammalian target of rapamycin (mTOR) signaling, which is involved in synaptic protein synthesis, could be a key factor controlling long-term potentiation in neuropathic pain conditions. Until now, there have been no reports that studied the role of mTOR signaling in the ACC involved in neuropathic pain. Therefore, this study was conducted to determine the relationship of mTOR signaling in the ACC and neuropathic pain. Male Sprague-Dawley rats were subjected to cannula implantation and nerve injury under pentobarbital anesthesia. Microinjection with rapamycin into the ACC was conducted under isoflurane anesthesia on postoperative day (POD) 7. A behavioral test was performed to evaluate mechanical allodynia, and optical imaging was conducted to observe the neuronal responses of the ACC to peripheral stimulation. Inhibition of mTOR by rapamycin reduced mechanical allodynia, down-regulated mTOR signaling in the ACC, and diminished the expressions of synaptic proteins which are involved in excitatory signaling, thereby reducing neuropathic pain-induced synaptic plasticity. These results suggest that inhibiting mTOR activity by rapamycin in the ACC could serve as a new strategy for treating or managing neuropathic pain before it develops into chronic pain.


Assuntos
Analgésicos/uso terapêutico , Giro do Cíngulo/patologia , Neuralgia/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Analgésicos/farmacologia , Animais , Estimulação Elétrica , Giro do Cíngulo/efeitos dos fármacos , Hiperalgesia/complicações , Hiperalgesia/patologia , Masculino , Microinjeções , Tecido Nervoso/lesões , Tecido Nervoso/patologia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Serina-Treonina Quinases TOR/metabolismo
18.
Nutr Neurosci ; 22(8): 587-595, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29286866

RESUMO

Although attention deficit hyperactivity disorder is associated with deficits in docosahexaenoic acid (DHA), an omega-3 fatty acid implicated in dopamine and glutamate synaptic plasticity, its role in neuroplastic brain changes that occur following repeated amphetamine (AMPH) treatment are not known. This study used pharmacological magnetic resonance imaging to investigate the impact of repeated AMPH exposure and alterations in brain DHA levels on AMPH-induced brain activation patterns. Male rats were fed a diet with no n-3 fatty acids (Deficient, DEF, n = 20), a diet fortified with preformed DHA (fish oil, FO, n = 20), or a control diet fortified with alpha-linolenic acid (n = 20) from P21 to P90. During adolescence (P40-60), one-half of each diet group received daily AMPH injections escalated weekly (0.5, 1.0, 2.5, 5.0 mg/kg/d) or drug vehicle. Following a 30-d abstinence period blood oxygen level dependent (BOLD) responses were determined in a 7 T Bruker Biospec system following an AMPH challenge (7.5 mg/kg, i.v). Postmortem erythrocyte and forebrain DHA composition were determined by gas chromatography. Compared with control rats, forebrain and erythrocyte DHA levels were significantly lower in DEF rats and significantly higher in FO rats. Across AMPH doses DEF rats exhibited greater locomotor activity compared to control and FO rats. In AMPH-naïve rats, the AMPH challenge increased BOLD activity in the substantia nigra and basal forebrain and no diet group differences were observed. In AMPH-pretreated control and FO rats, the AMPH challenge similarly increased BOLD activation in the bilateral caudate putamen, thalamus, and motor and cingulate cortices. In contrast, BOLD activation in AMPH-pretreated DEF rats was similar to AMPH-naïve DEF animals, and AMPH-pretreated DEF rats exhibited attenuated frontostriatal BOLD activation compared with AMPH-pretreated control and FO rats. These findings demonstrate that chronic escalating AMPH treatment induces enduring frontostriatal recruitment and that peri-adolescent deficits in brain DHA accrual impair this response.


Assuntos
Anfetamina/administração & dosagem , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Ácidos Docosa-Hexaenoicos/administração & dosagem , Animais , Prosencéfalo Basal/efeitos dos fármacos , Prosencéfalo Basal/fisiologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiologia , Ácidos Docosa-Hexaenoicos/metabolismo , Eritrócitos/metabolismo , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/fisiologia , Locomoção/efeitos dos fármacos , Imagem por Ressonância Magnética , Masculino , Córtex Motor/efeitos dos fármacos , Córtex Motor/fisiologia , Prosencéfalo/metabolismo , Ratos Long-Evans , Substância Negra/efeitos dos fármacos , Substância Negra/fisiologia , Tálamo/efeitos dos fármacos , Tálamo/fisiologia
19.
Artigo em Inglês | MEDLINE | ID: mdl-30222989

RESUMO

Orexin neurons are discretely localized within the lateral hypothalamus and have widespread projections into all areas of the brain. In addition, several lines of evidence specify that orexins may also participate in the regulation of a variety of affective and cognitive processes. The Orexin-1 receptor (OX1r) is distributed extensively throughout the prefrontal cortex (PFC). Delay-based decision- making is mediated largely by the orbitofrontal cortex (OFC) while effort- based decision-making is controlled by the anterior cingulated cortex (ACC). Hence, in the present study, a series of experiments were conducted to clarify the role of OX1r in the mPFC (ACC and/or OFC) in cost and benefit decision-making. The rats were trained in a delay and/or effort-based form of cost-benefit T-maze decision-making task. Two goal arms were different in the amount of accessible reward and cost. Before surgery, all animals were selecting the high reward arm and pay the cost on almost every trial. During the test days, the rats received local injections of either DMSO 20% /0.5 µl, as a vehicle, or SB334867 (3, 30 and 300 nM/0.5 µl), as a selective OX1r antagonist, within the ACC and/or OFC. The results of this study showed that the bilateral microinjection of SB334867 into ACC and/or OFC changed the preference to a low reward arm with no cost, indicating the role of OX1 receptors in cost and benefit decision- making. From these results, it can be implied that OX1 receptors in the mPFC play a crucial role for allowing the animal to evaluate and pay the cost to acquire greater rewards.


Assuntos
Tomada de Decisões/fisiologia , Giro do Cíngulo/metabolismo , Receptores de Orexina/metabolismo , Córtex Pré-Frontal/metabolismo , Animais , Benzoxazóis/farmacologia , Análise Custo-Benefício , Tomada de Decisões/efeitos dos fármacos , Giro do Cíngulo/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Naftiridinas , Antagonistas dos Receptores de Orexina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Psicotrópicos/farmacologia , Ratos Wistar , Recompensa , Ureia/análogos & derivados , Ureia/farmacologia
20.
Brain Res ; 1704: 187-195, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30339810

RESUMO

Cholinergic systems modulate synaptic transmission across the neuraxis and play an important role in higher brain function including cognition, arousal and nociception. The anterior cingulate cortex (ACC) is a fundamental brain region for nociception and chronic pain, and receives cholinergic projections mainly from basal forebrain. Recently, we found that the activation of muscarinic M1 receptors in the ACC produced antinociceptive behavior in response to mechanical stimulation. However, it has not been tested whether stimulating muscarinic receptors in the ACC can reduce mechanical hypersensitivity in animal models of chronic pain. Here, we tested whether the activation of muscarinic M1 receptors in the ACC can alleviate mechanical hypersensitivity in a nerve injury model. The activation of muscarinic M1/M4 receptors by McN-A-343 injected into the contralateral side of the ACC, but not into the ventral posterolateral nucleus, was found to dose-dependently reduce mechanical hypersensitivity 7 days following partial sciatic nerve ligation in rats. The reduction of mechanical hypersensitivity by McN-A-343, was blocked by a selective muscarinic M1 antagonist, but not a M4 receptor antagonist. Importantly, the nerve injury model did not change the protein expression of muscarinic M1 receptors in the ACC. Additionally, a type A γ-aminobutyric acid (GABAA) receptor agonist injected into the ACC reduced the mechanical hypersensitivity in this injury model. Finally, a GABAA receptor antagonist blocked the reduction of mechanical hypersensitivity by McN-A-343 in the injury model. Collectively, these results suggest that activations of muscarinic M1 receptors in the ACC reduce nerve injury-induced mechanical hypersensitivity through GABAergic transmission via GABAA receptors.


Assuntos
Cloreto de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamônio/farmacologia , Neurônios GABAérgicos/efeitos dos fármacos , Giro do Cíngulo/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Agonistas Muscarínicos/farmacologia , Traumatismos dos Nervos Periféricos/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Cloreto de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamônio/uso terapêutico , Animais , Neurônios GABAérgicos/metabolismo , Giro do Cíngulo/metabolismo , Giro do Cíngulo/fisiopatologia , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Masculino , Agonistas Muscarínicos/uso terapêutico , Traumatismos dos Nervos Periféricos/fisiopatologia , Ratos , Ratos Wistar , Nervo Isquiático/lesões , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismo
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