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1.
Nature ; 574(7779): 543-548, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645720

RESUMO

Multicellular organisms have co-evolved with complex consortia of viruses, bacteria, fungi and parasites, collectively referred to as the microbiota1. In mammals, changes in the composition of the microbiota can influence many physiologic processes (including development, metabolism and immune cell function) and are associated with susceptibility to multiple diseases2. Alterations in the microbiota can also modulate host behaviours-such as social activity, stress, and anxiety-related responses-that are linked to diverse neuropsychiatric disorders3. However, the mechanisms by which the microbiota influence neuronal activity and host behaviour remain poorly defined. Here we show that manipulation of the microbiota in antibiotic-treated or germ-free adult mice results in significant deficits in fear extinction learning. Single-nucleus RNA sequencing of the medial prefrontal cortex of the brain revealed significant alterations in gene expression in excitatory neurons, glia and other cell types. Transcranial two-photon imaging showed that deficits in extinction learning after manipulation of the microbiota in adult mice were associated with defective learning-related remodelling of postsynaptic dendritic spines and reduced activity in cue-encoding neurons in the medial prefrontal cortex. In addition, selective re-establishment of the microbiota revealed a limited neonatal developmental window in which microbiota-derived signals can restore normal extinction learning in adulthood. Finally, unbiased metabolomic analysis identified four metabolites that were significantly downregulated in germ-free mice and have been reported to be related to neuropsychiatric disorders in humans and mouse models, suggesting that microbiota-derived compounds may directly affect brain function and behaviour. Together, these data indicate that fear extinction learning requires microbiota-derived signals both during early postnatal neurodevelopment and in adult mice, with implications for our understanding of how diet, infection, and lifestyle influence brain health and subsequent susceptibility to neuropsychiatric disorders.


Assuntos
Extinção Psicológica/fisiologia , Medo/fisiologia , Metabolômica , Microbiota/fisiologia , Neurônios/fisiologia , Animais , Antibacterianos/farmacologia , Transtorno Autístico/metabolismo , Sangue/metabolismo , Cálcio/metabolismo , Líquido Cefalorraquidiano/química , Líquido Cefalorraquidiano/metabolismo , Sinais (Psicologia) , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/patologia , Espinhas Dendríticas/fisiologia , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Fezes/química , Vida Livre de Germes , Indicã/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microbiota/efeitos dos fármacos , Microbiota/imunologia , Inibição Neural , Neuroglia/patologia , Neuroglia/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/imunologia , Neurônios/patologia , Fenilpropionatos/metabolismo , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/imunologia , Córtex Pré-Frontal/fisiologia , Esquizofrenia/metabolismo , Transcriptoma , Nervo Vago/fisiologia
2.
Nat Commun ; 10(1): 3934, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477694

RESUMO

Drug addiction is a chronic relapsing disorder of compulsive drug use. Studies of the neurobehavioral factors that promote drug relapse have yet to produce an effective treatment. Here we take a different approach and examine the factors that suppress-rather than promote-relapse. Adapting Pavlovian procedures to suppress operant drug response, we determined the anti-relapse action of environmental cues that signal drug omission (unavailability) in rats. Under laboratory conditions linked to compulsive drug use and heightened relapse risk, drug omission cues suppressed three major modes of relapse-promotion (drug-predictive cues, stress, and drug exposure) for cocaine and alcohol. This relapse-suppression is, in part, driven by omission cue-reactive neurons, which constitute small subsets of glutamatergic and GABAergic cells, in the infralimbic cortex. Future studies of such neural activity-based cellular units (neuronal ensembles/memory engram cells) for relapse-suppression can be used to identify alternate targets for addiction medicine through functional characterization of anti-relapse mechanisms.


Assuntos
Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Sinais (Psicologia) , Neurônios/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Alcoolismo/fisiopatologia , Alcoolismo/prevenção & controle , Animais , Cocaína/administração & dosagem , Comportamento Compulsivo/fisiopatologia , Comportamento Compulsivo/prevenção & controle , Condicionamento Operante/fisiologia , Inibidores da Captação de Dopamina/farmacologia , Masculino , Córtex Pré-Frontal/fisiopatologia , Ratos Long-Evans , Ratos Sprague-Dawley , Ratos Transgênicos , Recidiva , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/prevenção & controle
3.
BMC Complement Altern Med ; 19(1): 215, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412844

RESUMO

BACKGROUND: Mounting evidence indicates that the cerebral cortex is an important physiological system of emotional activity, and its dysfunction may be the main cause of stress. Glutamate is the primary excitatory neurotransmitter in the central nervous system (CNS), which initiates rapid signal transmission in the synapse before its reuptake into the surrounding glia, specifically astrocytes (ASTs). The astrocytic excitatory amino acid transporters 1 (EAAT1) and 2 (EAAT2) are the major transporters that take up synaptic glutamate to maintain optimal extracellular glutamic levels, thus preventing accumulation in the synaptic cleft and ensuing excitotoxicity. Growing evidence has shown that excitotoxicity is associated with depression. Therefore, we hypothesized that the underlying antidepressant-like mechanism of Xiaoyaosan (XYS), a Chinese herbal formula, may be related to the regulation of astrocytic EAATs. Therefore, we studied the antidepressant mechanism of XYS on the basis of EAAT dysfunction in ASTs. METHODS: Eighty adult C57BL/6 J mice were randomly divided into 4 groups: a control group, a chronic unpredictable mild stress (CUMS) group, a Xiaoyaosan (XYS) treatment group and a fluoxetine hydrochloride (Flu) treatment group. Except for the control group, mice in the other groups all received chronic unpredictable mild stress for 21 days. Mice in the control and CUMS groups received gavage administration with 0.5 mL of normal saline (NS) for 21 days, and mice in the XYS and Flu treatment groups were administered dosages of 0.25 g/kg/d and 2.6 mg/kg/d by gavage. The effects of XYS on the depressive-like behavioral tests, including the open field test (OFT), forced swimming test (FST) and sucrose preference test (SPT), were examined. The glutamate (Glu) concentrations of the prefrontal cortex (PFC) were detected with colorimetry. The morphology of neurons in the PFC was observed by Nissl staining. The expression of glial fibrillary acidic protein (GFAP), NeuN, EAAT1 and EAAT2 proteins in the PFC of mice was detected by using Western blotting and immunohistochemistry. Quantitative real-time PCR (qPCR) was used to detect the expression of the GFAP, NeuN, EAAT1 and EAAT2 genes in the PFC of mice. RESULTS: The results of behavioral tests showed that CUMS-induced mice exhibited depressive-like behavior, which could be improved in some tests with XYS and Flu treatment. Immunohistochemistry and Western blot analysis showed that the protein levels of GFAP, NeuN, EAAT1 and EAAT2 in the PFC of CUMS mice were significantly lower than those in the control group, and these changes could be reversed by XYS and Flu. The results of qPCR analysis showed that the expression of GFAP, NeuN, EAAT1 and EAAT2 mRNAs in the PFC of CUMS mice was not significantly changed, with the exception of EAAT2, compared with that of the control group, while the expression of the above mRNAs was significantly higher in the XYS and Flu groups than that in the CUMS group. CONCLUSION: XYS may exert antidepressant-like effects by improving the functions of AST and EAATs and attenuating glutamate-induced neuronal damage in the frontal cortex.


Assuntos
Antidepressivos/administração & dosagem , Astrócitos/efeitos dos fármacos , Depressão/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Transportador 1 de Aminoácido Excitatório/metabolismo , Transportador 2 de Aminoácido Excitatório/metabolismo , Córtex Pré-Frontal/citologia , Animais , Comportamento Animal , Depressão/genética , Depressão/metabolismo , Modelos Animais de Doenças , Transportador 1 de Aminoácido Excitatório/genética , Transportador 2 de Aminoácido Excitatório/genética , Proteína Glial Fibrilar Ácida/metabolismo , Ácido Glutâmico/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/efeitos dos fármacos
4.
Life Sci ; 234: 116751, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31415771

RESUMO

AIMS: The present study aims to investigate the impacts of olfactory bulbectomy (OBX) on urinary metabolic profile and tryptophan metabolites in prefrontal cortex (PFC) of rats, and to explore the regulation effects of fluoxetine. MAIN METHODS: OBX model was developed by aspiration of olfactory bulbs. After fluoxetine treatment (10 mg/kg) for 14 days, urine samples were collected and behavior tests were applied. Tryptophan (TRP) metabolites and neurotransmitters in PFC were determined by prominence ultrafast liquid chromatography-QTRAP-mass spectrometry, and tryptophan hydroxylase 2 (TPH2) and indoleamine-2,3-dioxygenase 1 (IDO1) were evaluated by western blot. Urinary metabolites were analyzed by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry-based metabonomics strategy. KEY FINDING: OBX rats showed hyperlocomotion in open field, hyperactivity in open arm and despair status, and fluoxetine reserved these behavioral abnormalities. The levels of TRP, 5-HIAA, 5-HIAA/5-HT ratio and DA increased, while kynurenine and 5-HT decreased in PFC of OBX rats. The activities of TPH2 and IDO1were inhibited after OBX. Twenty-six altered metabolites were identified as potential biomarkers in OBX rats involved in tryptophan metabolism, gut microbiota metabolism, energy metabolism, purine metabolism, ascorbate and aldarate metabolism, and tyrosine metabolism. Among them, 15 abnormal metabolites were corrected by fluoxetine to some extent. SIGNIFICANCE: Our results revealed that urinary metabolic profile changed greatly in OBX rats, and identified biomarkers might be helpful for the diagnosis of agitated depression. The regulation effects of fluoxetine on urinary metabolic profile and tryptophan metabolites in PFC might contribute to its antidepressant action in OBX rats.


Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Depressão/tratamento farmacológico , Depressão/metabolismo , Fluoxetina/uso terapêutico , Metaboloma/efeitos dos fármacos , Animais , Antidepressivos de Segunda Geração/farmacologia , Depressão/urina , Modelos Animais de Doenças , Fluoxetina/farmacologia , Masculino , Bulbo Olfatório/cirurgia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos Sprague-Dawley , Triptofano/metabolismo
5.
Biol Pharm Bull ; 42(8): 1433-1436, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366880

RESUMO

The medial prefrontal cortex (mPFC) plays critical roles in the development of cocaine addiction. Numerous studies have reported about the effects of cocaine on neuronal and synaptic activities in the nucleus accumbens and ventral tegmental area, which are brain regions associated with cocaine addiction; however, a limited number of studies have reported the effect of cocaine on mPFC neuronal activity. In this study, using whole-cell patch-clamp recordings in brain slices, we present that under the condition where synaptic transmission is enhanced by increasing extracellular K+ concentration, cocaine significantly reduced the frequency but not amplitude of spontaneous excitatory postsynaptic currents. These findings suggest that cocaine exposure could be a trigger to induce hypofrontality, which is related to the compulsive craving for cocaine use.


Assuntos
Cocaína/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Animais , Feminino , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/fisiologia , Células Piramidais/fisiologia , Transmissão Sináptica/efeitos dos fármacos
6.
Neurochem Res ; 44(9): 2068-2080, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31317507

RESUMO

The mechanisms underlying chronic and neuropathic pain pathology involve peripheral and central sensitisation. The medial prefrontal cortex (mPFC) seems to participate in pain chronification, and glutamatergic neurotransmission may be involved in this process. Thus, the aim of the present work was to investigate the participation of the prelimbic (PrL) area of the mPFC in neuropathic pain as well as the role of N-methyl D-aspartate (NMDA) glutamate receptors in neuropathic pain induced by a modified sciatic nerve chronic constriction injury (CCI) protocol in Wistar rats. Neural inputs to the PrL cortex were inactivated by intracortical treatment with the synapse blocker cobalt chloride (CoCl2, 1.0 mM/200 nL) 7, 14, 21, or 28 days after the CCI or sham procedure. The glutamatergic agonist NMDA (0.25, 1 or 4 nmol) or the selective NMDA receptor antagonist LY235959 (2, 4 or 8 nmol) was microinjected into the PrL cortex 21 days after surgery. CoCl2 administration in the PrL cortex decreased allodynia 21 and 28 days after CCI. NMDA at 1 and 4 nmol increased allodynia, whereas LY235959 decreased mechanical allodynia at the highest dose (8 nmol) microinjected into the PrL cortex. These findings suggest that NMDA receptors in the PrL cortex participate in enhancing the late phase of mechanical allodynia after NMDA-induced increases and LY235959-induced decreases in allodynia 21 days after CCI. The glutamatergic system potentiates chronic neuropathic pain by NMDA receptor activation in the PrL cortex. Mechanism of neuropathic pain. The infusion of CoCl2, a synapse activity blocker, into the prelimbic (PrL) division of the medial prefrontal cortex (mPFC) decreased the severity of mechanical allodynia, showing the late participation of the limbic cortex. The glutamatergic system potentiates chronic neuropathic pain via NMDA receptor activation in the PrL cortex.


Assuntos
Neuralgia/metabolismo , Nervos Periféricos/metabolismo , Córtex Pré-Frontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Cobalto/farmacologia , Hiperalgesia/tratamento farmacológico , Isoquinolinas/farmacologia , Masculino , N-Metilaspartato/farmacologia , Neuralgia/tratamento farmacológico , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Córtex Pré-Frontal/efeitos dos fármacos , Ratos Wistar , Transmissão Sináptica/efeitos dos fármacos
7.
Sci Total Environ ; 689: 1012-1022, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31280147

RESUMO

The etiology of depression is not known, it is thought that endocrine-disrupting chemicals (EDCs) contribute to the disease. Results of our previous research have shown that nonylphenol (NP), a well-known EDC, has neurotoxic effects, however, whether NP can induce depressive behavior by affecting synaptic plasticity has not yet been clearly elucidated. The depressive behavior induced by subchronic exposure to NP and its effect on the neuronal synaptic plasticity in rats are dynamically observed. Thirty Sprague-Dawley rats were randomly divided into 3 groups: control group (C, corn oil), NP group (NP, 4 mg/kg), and depression model group (D, corticosterone 20 mg/kg). There were 8 rats in each group. The depressive behavior of rats was tested by sucrose preference test, open-field test, and forced swimming test once a month for 3 months. The serum levels of brain-derived neurotrophic factor (BDNF) and corticosterone were detected by ELISA assay, and cellular morphological changes were observed by hematoxylin-eosin (HE) staining. The number of nerve cells, the length of dendrites, and the density of dendritic spines were observed by Golgi staining, and the synaptic cleft width, the postsynaptic density (PSD) thickness, and the synaptic interface curvature were observed by transmission electron microscope. Compared with the control group, the consumption of sucrose solution decreased in the NP group at the 2nd and 3rd month compared to the 1st month (F = 9.887, P = 0.002). The number of central square entries, the central square duration, and the total distance of movement were all decreased, and the decreasing degrees at the 3rd month were greater than those at the 1st month (F = 21.191, P < 0.001; F = 9.836, P = 0.002). The time of immobility for the NP group at the 1st month was higher than that in the control group (F = 6.912, P = 0.002). The expression of BDNF in the NP-treated group was higher than the control, while the expression of corticosterone in the NP-treated group was lower than the control. In the NP group, the cytoplasm of nerve cells contracted and appeared disordered. The neuron arrangement was disordered, and the number of cells, the length of the apex, the length of the basal dendrites, and the dendritic spine density were all lower in the NP group than those in the control group. The PSD thickness, the synaptic cleft width, and synaptic interface curvatures were all decreased in the NP group when compared to the control group. Subchronic exposure to 4 mg/kg NP led to depressive behavior in rats, and the depressive behavior and alterations in synaptic plasticity were more obvious with longer exposure time.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Depressão/fisiopatologia , Disruptores Endócrinos/toxicidade , Glucocorticoides/sangue , Plasticidade Neuronal/efeitos dos fármacos , Fenóis/toxicidade , Animais , Depressão/induzido quimicamente , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
8.
Psychopharmacology (Berl) ; 236(7): 2155-2171, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31161451

RESUMO

RATIONALE: Exercise shows promise as a treatment option for addiction; but in order to prevent relapse, it may need to be introduced early in the course of treatment. OBJECTIVE: We propose that exercise, by upregulating dorsal medial prefrontal cortex (dmPFC)-nucleus accumbens (NAc) transmission, offsets deficits in pathways targeting glutamate, BDNF, and dopamine during early abstinence, and in doing so, normalizes neuroadaptations that underlie relapse. METHODS: We compared the effects of exercise (wheel running, 2-h/day) during early (days 1-7), late (days 8-14), and throughout abstinence (days 1-14) to sedentary conditions on cocaine-seeking and gene expression in the dmPFC and NAc core of male rats tested following 24-h/day extended-access cocaine (up to 96 infusions/day) or saline self-administration and protracted abstinence (15 days). Based on these data, we then used site-specific manipulation to determine whether dmPFC metabotropic glutamate receptor5 (mGlu5) underlies the efficacy of exercise. RESULTS: Exercise initiated during early, but not late abstinence, reduced cocaine-seeking; this effect was strongly associated with dmPFC Grm5 expression (gene encoding mGlu5), and modestly associated with dmPFC Grin1 and Bdnf-IV expression. Activation of mGlu5 in the dmPFC during early abstinence mimicked the efficacy of early-initiated exercise; however, inhibition of these receptors prior to the exercise sessions did not block its efficacy indicating that there may be redundancy in the mechanisms through which exercise reduces cocaine-seeking. CONCLUSION: These findings indicate that addiction treatments, including exercise, should be tailored for early versus late phases of abstinence since their effectiveness will vary over abstinence due to the dynamic nature of the underlying neuroadaptations.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/metabolismo , Transtornos Relacionados ao Uso de Cocaína/terapia , Cocaína/administração & dosagem , Condicionamento Físico Animal/fisiologia , Córtex Pré-Frontal/metabolismo , Receptor de Glutamato Metabotrópico 5/metabolismo , Animais , Comportamento Aditivo/metabolismo , Comportamento Aditivo/prevenção & controle , Comportamento Aditivo/psicologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtornos Relacionados ao Uso de Cocaína/psicologia , Inibidores da Captação de Dopamina/administração & dosagem , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Condicionamento Físico Animal/métodos , Condicionamento Físico Animal/psicologia , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Recidiva , Corrida/fisiologia , Corrida/psicologia , Autoadministração
9.
Environ Toxicol Pharmacol ; 70: 103202, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173966

RESUMO

Cannabidiol (CBD) exhibits significant efficacy in mental and inflammatory diseases. Several studies have recently reported on the rapid antidepressant-like effects of CBD, suggesting that CBD is a potential anti-depressant or anti-stress drug. However, CBD is mainly administered orally or by inhalation with poor bioavailability, resulting in high costs. We aim to explore the efficacy of long-term periodic administration of CBD in chronic mild stress (CMS) via two routes and its pharmacokinetics. We treated ICR mice with CBD administered orally and intravenously and then determined the kinetic constants. A single bolus intravenous injection of CBD resulted in a half-life of 3.9 h, mean residence time of 3.3 h, and oral bioavailability of about 8.6%. The antidepressant-like effects of periodically administered CBD on the chronic mild stress mouse model are evaluated. Results demonstrated that such treatment at a high dose of 100 mg/kg CBD (p.o.) or a low dose of 10 mg/kg CBD (i.v.), elicited significant antidepressant-like behavioral effects in forced swim test, following increased mRNA expression of brain-derived neurotrophic factor (BDNF) and synaptophysin in the prefrontal cortex and the hippocampus. Our findings are expected to provide a reference for the development of intravenous antidepressant formulations of CBD.


Assuntos
Antidepressivos/administração & dosagem , Antidepressivos/farmacocinética , Canabidiol/administração & dosagem , Canabidiol/farmacocinética , Estresse Psicológico/tratamento farmacológico , Administração Intravenosa , Administração Oral , Animais , Antidepressivos/sangue , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/genética , Proteínas de Ligação ao Cálcio/genética , Canabidiol/sangue , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos Endogâmicos ICR , Proteínas dos Microfilamentos/genética , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Estresse Psicológico/genética , Sinaptofisina/genética
10.
J Mol Neurosci ; 69(1): 60-68, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31127538

RESUMO

In this study, we aimed to establish the effects of chronic corticosterone (CORT) and ethanol administration on mood-related behaviour and the levels of mature brain-derived neurotrophic factor (mBDNF) and its precursor protein proBDNF in mice. C57BL6 male and female mice received drinking water (n = 22), 1% ethanol in drinking water (n = 16) or 100 µg/ml corticosterone in drinking water (containing 1% ethanol, n = 18) for 4.5 weeks. At the end of experimental protocol, the open field test (OFT) and elevated plus maze test were performed. Brain and adrenal tissues were collected and mBDNF and proBDNF were measured by ELISA assays. We found that the mice fed with corticosterone and ethanol developed anxiety-like behaviours as evidenced by reduced time in the central zone in the OFT compared with the control group. Both proBDNF and mBDNF were significantly decreased in the corticosterone and ethanol groups compared with the control group in the prefrontal cortex, hippocampus, hypothalamus and adrenal. The ratio of proBDNF/mBDNF in prefrontal cortex in the corticosterone group was increased compared with the ethanol group. Our data suggest that the ratio of proBDNF/mBDNF is differentially regulated in different tissues. Ethanol and corticosterone downregulate both mBDNF and proBDNF and alter the balance of proBDNF/mBDNF in some tissues. In conclusion, the ethanol and corticosterone may cause abnormal regulation of mBDNF and proBDNF which may lead to mood disorders.


Assuntos
Afeto , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corticosterona/farmacologia , Etanol/farmacologia , Aprendizagem em Labirinto , Córtex Pré-Frontal/efeitos dos fármacos , Animais , Depressores do Sistema Nervoso Central/farmacologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Hipotálamo/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia
11.
Neurobiol Learn Mem ; 162: 15-22, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31047996

RESUMO

Reciprocal connections between the mediodorsal thalamic nucleus (MD) and the prefrontal cortex (PFC) are important for memory processes. Since the co-abuse of nicotine and ethanol affects memory formation, this study investigated the effect of nitric oxide inhibition in the MD on memory retrieval induced by co-administration of nicotine and ethanol. Subsequently, western blot analysis was used to evaluate how this change would alter the PFC pCREB/CREB signaling pathway. Male Wistar rats were bilaterally cannulated into the MD and the memory retrieval was measured by passive avoidance task. Intraperitoneal (i.p.) administration of ethanol (1 g/kg, i.p) 30 min before the test impaired memory retrieval and caused ethanol-induced amnesia. Subcutaneous (s.c.) administration of nicotine (0.05-0.2 mg/kg, s.c.) prevented ethanol-induced amnesia and improved memory retrieval. Intra-MD microinjection of a nitric oxide synthase (NOS) inhibitor, L-NAME (0.5-1 µg/rat) inhibited the improving effect of nicotine (0.2 mg/kg, s.c.) on ethanol-induced amnesia, while intra-MD microinjection of a precursor of nitric oxide, l-arginine (0.25-1 µg/rat), potentiated such effect. Noteworthy, intra-MD microinjection of the same doses of L-NAME or l-arginine by itself had no effect on memory retrieval. Furthermore, intra-MD microinjection of L-NAME (0.05, 0.1 and 0.3 µg/rat) reversed the l-arginine improving effect on nicotine response. Successful memory retrieval significantly increased the p-CREB/CREB ratio in the PFC tissue. Ethanol-induced amnesia, however, decreased this ratio in the PFC while the co-administration of nicotine and ethanol increased the PFC CREB signaling. Interestingly, the inhibitory effect of L-NAME and the potentiating effect of l-arginine on nicotine response were associated with the decrease and increase of the PFC p-CREB/CREB ratio respectively. It can be concluded that MD-PFC connections are involved in the combined effects of nicotine and ethanol on memory retrieval. The mediodorsal thalamic NO system possibly mediated this interaction via the pCREB/CREB signaling pathways in the PFC.


Assuntos
Etanol/farmacologia , Núcleo Mediodorsal do Tálamo/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Nicotina/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Córtex Pré-Frontal/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Inibidores Enzimáticos/farmacologia , Masculino , Núcleo Mediodorsal do Tálamo/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Agonistas Nicotínicos/farmacologia , Óxido Nítrico/metabolismo , Fosforilação/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Wistar
12.
Psychopharmacology (Berl) ; 236(9): 2747-2759, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31037409

RESUMO

RATIONALE: Modafinil is increasingly used by healthy humans as a neuroenhancer in order to improve cognitive functioning. Research on the effects of modafinil on cognition yielded most consistent findings for complex tasks relying on the prefrontal cortex (PFC). OBJECTIVES: The present randomized placebo-controlled double-blind crossover study aimed to investigate the effect of a single dose of modafinil (200 mg) on everyday moral decision making and its neural correlates, which have been linked to the ventro- and dorsomedial PFC. METHODS: Healthy male study participants were presented with short stories describing everyday moral or neutral dilemmas. Each moral dilemma required a decision between a personal desire and a moral standard, while the neutral dilemmas required decisions between two personal desires. The participants underwent this task twice, once under the influence of modafinil and once under placebo. Brain activity associated with the processing of the dilemmas was assessed by means of functional magnetic resonance imaging. RESULTS: For the processing of moral vs. neutral dilemmas, activations were found in a network of brain regions linked to social cognitive processes including, among others, the bilateral medial PFC, the insula, and the precuneus. Modafinil was found to increase the number of moral decisions and had no effect on brain activity associated with dilemma processing. Exploratory analyses revealed reduced response-locked activity in the dorsomedial PFC for moral compared to neutral dilemmas under modafinil, but not under placebo. CONCLUSIONS: The results are discussed in terms of altered predictions of others' emotional states under modafinil, possibly due to higher processing efficiency.


Assuntos
Tomada de Decisões/efeitos dos fármacos , Imagem por Ressonância Magnética/métodos , Modafinila/farmacologia , Princípios Morais , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/diagnóstico por imagem , Adulto , Mapeamento Encefálico/métodos , Estimulantes do Sistema Nervoso Central/farmacologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Estudos Cross-Over , Tomada de Decisões/fisiologia , Método Duplo-Cego , Emoções/efeitos dos fármacos , Emoções/fisiologia , Humanos , Masculino , Adulto Jovem
13.
Braz J Med Biol Res ; 52(5): e8334, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31038580

RESUMO

Studies have shown that an injection with the histamine H4 receptor agonist VUF-8430 modulates emotional memory processes. In the present study, the aim was to verify if intraperitoneal (ip) injection of VUF-8430 (500 ng/kg) in mice affects the synthesis of proteins required for memory consolidation processes by activating the phosphorylation of CREB (pCREB) in classical structures linked to emotional memory (prefrontal cortex, amygdala, and hippocampus) and the cerebellar vermis, a structure that has also been recently implicated in emotional memory. The results obtained using western blot analysis demonstrated that VUF-8430 induced a decrease in CREB and pCREB levels in the cerebellar vermis and prefrontal cortex, suggesting that this dose impaired the activation of cell signaling pathways in these structures. There was no change in protein expression in the amygdala and hippocampus. Our results are preliminary, and further investigations are needed to investigate the role of the H4 receptors in the central nervous system.


Assuntos
Vermis Cerebelar/metabolismo , Memória/fisiologia , Córtex Pré-Frontal/metabolismo , Receptores Histamínicos H4/metabolismo , Animais , Vermis Cerebelar/efeitos dos fármacos , Modelos Animais de Doenças , Emoções , Hipocampo , Antagonistas dos Receptores Histamínicos/farmacologia , Masculino , Consolidação da Memória/fisiologia , Camundongos , Fosforilação , Córtex Pré-Frontal/efeitos dos fármacos , Estresse Fisiológico
14.
Neuroimage ; 197: 575-585, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31075393

RESUMO

The primary psychoactive compound in cannabis, Δ9-tetrahydrocannabinol (THC), binds to cannabinoid receptors (CB1) present in high concentrations in the prefrontal cortex (PFC). It is unknown whether the PFC hemodynamic response changes with THC intoxication. We conducted the first double-blind, placebo-controlled, cross-over study of the effect of THC intoxication on functional near infrared spectroscopy (fNIRS) measures of PFC activation. Fifty-four adult, regular (at least weekly) cannabis users received a single oral dose of synthetic THC (dronabinol; 5-50 mg, dose individually tailored to produce intoxication) and identical placebo on two visits at least one week apart. fNIRS recordings were obtained during a working memory task (N-Back) at three timepoints: before THC/placebo, at 100 min (when peak effects were expected), and at 200 min after THC/placebo administration. Functional data were collected using a continuous-wave NIRS device, with 8 sources and 7 detectors arrayed over the forehead, resulting in 20 channels covering PFC regions. Participants also completed frequent heart rate measures and subjective ratings of intoxication. Approximately half of participants reported significant intoxication. Intoxication ratings were not correlated with dose of THC. Increases in heart rate significantly correlated with intoxication ratings after THC dosing. Results indicated that 100 min after THC administration, oxygenated hemoglobin (HbO) response significantly increased from pre-dose HbO levels throughout the PFC in participants who reported significant intoxication. Changes in HbO response significantly correlated with self-reported intoxication at 100 min after THC administration. Among those who reported intoxication, HbO response decreased at 200 min after THC, when intoxication had largely resolved, compared to the peak THC time point. This study demonstrates that THC intoxication causes increased PFC activity, and fNIRS of the PFC can measure this effect. Increased neural activation in PFC represents a potential biomarker for cannabis intoxication.


Assuntos
Dronabinol/efeitos adversos , Abuso de Maconha/diagnóstico , Córtex Pré-Frontal/efeitos dos fármacos , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino
15.
Psychopharmacology (Berl) ; 236(11): 3183-3195, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31139875

RESUMO

RATIONALE: Androgen deprivation therapy (ADT) is an effective treatment for prostate cancer, but induces profound cognitive impairment. Little research has addressed mechanisms underlying these deficits or potential treatments. This is an unmet need to improve quality of life for prostate cancer survivors. OBJECTIVES: We investigated mechanisms of cognitive impairment after ADT in rats and potential utility of the multimodal serotonin-targeting drug, vortioxetine, to improve the impairment, as vortioxetine has specific efficacy against cognitive impairment in depression. METHODS: Male Sprague-Dawley rats were surgically castrated. Vortioxetine (28 mg/kg/day) was administered in the diet. The attentional set-shifting test was used to assess medial prefrontal cortex (mPFC) executive function. Afferent-evoked field potentials were recorded in the mPFC of anesthetized rats after stimulating the ventral hippocampus (vHipp) or medial dorsal thalamus (MDT). Gene expression changes were assessed by microarray. Effects of vortioxetine on growth of prostate cancer cells were assessed in vitro. RESULTS: ADT impaired cognitive set shifting and attenuated responses evoked in the mPFC by the vHipp afferent, but not the MDT. Both the cognitive impairment and attenuated vHipp-evoked responses were reversed by chronic vortioxetine treatment. Preliminary investigation of gene expression in the mPFC indicates that factors involved in neuronal plasticity and synaptic transmission were down-regulated by castration and up-regulated by vortioxetine in castrated animals. Vortioxetine neither altered the growth of prostate cancer cells in vitro nor interfered with the antiproliferative effects of the androgen antagonist, enzalutamide. CONCLUSIONS: These results suggest that vortioxetine may be useful in mitigating cognitive impairment associated with ADT for prostate cancer.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Disfunção Cognitiva/metabolismo , Orquiectomia/efeitos adversos , Córtex Pré-Frontal/metabolismo , Neoplasias da Próstata/metabolismo , Vortioxetina/uso terapêutico , Antagonistas de Androgênios/farmacologia , Animais , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/psicologia , Relação Dose-Resposta a Droga , Masculino , Orquiectomia/psicologia , Orquiectomia/tendências , Córtex Pré-Frontal/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Vortioxetina/farmacologia
16.
Nihon Yakurigaku Zasshi ; 153(5): 219-223, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31092754

RESUMO

The development and persistence of drug addiction are associated with the activation and adaptation of the brain reward circuitry, which consists of dopaminergic projection from the ventral tegmental area to the nucleus accumbens (NAc) and the medial prefrontal cortex (mPFC). In cocaine addiction, cocaine-induced activation and neuroplasticity in the brain reward circuitry may contribute to the acquisition and expression of rewarding memory of cocaine, which is critical for the reinstatement of cocaine seeking. However, it remains unclear which neuronal types causally contribute to the retrieval of cocaine-associated rewarding memory. To address this issue, we used DREADD (Designer Receptors Exclusively Activated by Designer Drugs) technology. To selectively suppress mPFC excitatory neurons, we infused an adeno-associated virus (AAV5 or AAV-DJ) vector expressing hM4Di, an inhibitory DREADD, under the control of CaMKII promotor into the mPFC of wildtype mice. To selectively suppress GABAergic neurons, we infused a Cre-dependent AAV (AAV5 or AAV-DJ) vector expressing hM4Di into the mPFC of GAD67-Cre mice or the NAc of vGAT-Cre mice. We found that, in cocaine conditioned place preference paradigm, the activity of mPFC pyramidal and NAc GABAergic neurons is causally related to the retrieval of cocaine-associated memory. The findings suggest that the mPFC-NAc circuit can be a potential therapeutic target for the drug addiction.


Assuntos
Cocaína/farmacologia , Neurônios GABAérgicos/efeitos dos fármacos , Vetores Genéticos , Memória , Recompensa , Animais , Dependovirus , Camundongos , Núcleo Accumbens/citologia , Núcleo Accumbens/efeitos dos fármacos , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos
17.
Neuroscience ; 410: 128-139, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31095985

RESUMO

Transient ischemic attack (TIA) represents brief neurological dysfunction of vascular origin without detectable infarction. Despite major clinical relevance characterization of post-TIA molecular changes using appropriate experimental model is lacking and no therapeutic agent has been established yet. Neurosteroid dehydroepiandrosterone (DHEA) arose as one of the candidates for cerebral ischemia treatment but its effects on TIA-like condition remain unknown. Seeking an animal model applicable for investigation of molecular alterations in mild ischemic conditions such as TIA, 15-min bilateral common carotid artery occlusion with 24-h reperfusion was performed to induce ischemia/ reperfusion (I/R) injury in adult male Wistar rats. Additionally, effects of 4-h post-operative DHEA treatment (20 mg/kg) were investigated in physiological and I/R conditions in hippocampus (HIP) and prefrontal cortex (PFC). The study revealed absence of sensorimotor deficits, cerebral infarcts and neurodegeneration along with preserved HIP and PFC overall neuronal morphology and unaltered malondialdehyde and reduced glutathione level following I/R and/or DHEA treatment. I/R induced nitric oxide burst in HIP and PFC was accompanied with increased neuronal nitric oxide synthase protein level exclusively in HIP. DHEA had no effects in physiological conditions, while increase of Bax/Bcl2 ratio and dissipation of mitochondrial membrane potential in treated I/R group suggested DHEA-mediated exacerbation of post-ischemic changes that might lead to pro-apoptotic events in HIP. Interestingly, DHEA restored I/R-induced NO to the control level in PFC. Obtained results indicated that I/R may serve as an appropriate model for investigation of molecular changes and treatment outcome following mild ischemic conditions such as TIA.


Assuntos
Doenças das Artérias Carótidas/metabolismo , Artéria Carótida Primitiva/metabolismo , Desidroepiandrosterona/administração & dosagem , Mediadores da Inflamação/metabolismo , Ataque Isquêmico Transitório/metabolismo , Adjuvantes Imunológicos/administração & dosagem , Animais , Doenças das Artérias Carótidas/tratamento farmacológico , Doenças das Artérias Carótidas/patologia , Artéria Carótida Primitiva/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Ataque Isquêmico Transitório/tratamento farmacológico , Ataque Isquêmico Transitório/patologia , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Ratos , Ratos Wistar , Resultado do Tratamento
18.
Biosci Biotechnol Biochem ; 83(9): 1756-1765, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31119994

RESUMO

Depressive disorders are partly caused by chronic inflammation through the kynurenine (KYN) pathway. Preventive intervention using anti-inflammatory reagents may be beneficial for alleviating the risk of depression. In this study, we focused on the Japanese local citrus plant, Citrus tumida hort. ex Tanaka (C. tumida; CT), which contains flavonoids such as hesperidin that have anti-inflammatory actions. The dietary intake of 5% immature peels of CT fruits slightly increased stress resilience in a subchronic and mild social defeat (sCSDS) model in mice. Moreover, the dietary intake of 0.1% hesperidin significantly increased stress resilience and suppressed KYN levels in the hippocampus and prefrontal cortex in these mice. In addition, KYN levels in the hippocampus and prefrontal cortex were significantly correlated with the susceptibility to stress. In conclusion, these results suggest that dietary hesperidin increases stress resilience by suppressing the augmentation of KYN signaling under sCSDS.


Assuntos
Citrus/química , Dieta , Hesperidina/administração & dosagem , Hipocampo/efeitos dos fármacos , Cinurenina/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Resiliência Psicológica/efeitos dos fármacos , Comportamento Social , Estresse Psicológico/prevenção & controle , Animais , Comportamento Animal , Corticosterona/sangue , Hesperidina/farmacologia , Hipocampo/metabolismo , Interleucina-1beta/sangue , Interleucina-6/sangue , Cinurenina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Córtex Pré-Frontal/metabolismo , Triptofano/sangue
19.
Exp Brain Res ; 237(7): 1593-1614, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31079238

RESUMO

Antidepressant drugs are a standard biological treatment for various neuropsychiatric disorders, yet relatively little is known about their electrophysiologic and synaptic effects on mood systems that set moment-to-moment emotional tone. In vivo electrical recording of local field potentials (LFPs) and single neuron spiking has been crucial for elucidating important details of neural processing and control in many other systems, and yet electrical approaches have not been broadly applied to the actions of antidepressants on mood-related circuits. Here we review the literature encompassing electrophysiologic effects of antidepressants in animals, including studies that examine older drugs, and extending to more recently synthesized novel compounds, as well as rapidly acting antidepressants. The existing studies on neuromodulator-based drugs have focused on recording in the brainstem nuclei, with much less known about their effects on prefrontal or sensory cortex. Studies on neuromodulatory drugs have moreover focused on single unit firing patterns with less emphasis on LFPs, whereas the rapidly acting antidepressant literature shows the opposite trend. In a synthesis of this information, we hypothesize that all classes of antidepressants could have common final effects on limbic circuitry. Whereas NMDA receptor blockade may induce a high powered gamma oscillatory state via direct and fast alteration of glutamatergic systems in mood-related circuits, neuromodulatory antidepressants may induce similar effects over slower timescales, corresponding with the timecourse of response in patients, while resetting synaptic excitatory versus inhibitory signaling to a normal level. Thus, gamma signaling may provide a biomarker (or "neural readout") of the therapeutic effects of all classes of antidepressants.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Ritmo Gama/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Antidepressivos/farmacologia , Depressão/fisiopatologia , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Fenômenos Eletrofisiológicos/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Ritmo Gama/fisiologia , Humanos , Córtex Pré-Frontal/fisiopatologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia
20.
Science ; 364(6436)2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30975859

RESUMO

The neurobiological mechanisms underlying the induction and remission of depressive episodes over time are not well understood. Through repeated longitudinal imaging of medial prefrontal microcircuits in the living brain, we found that prefrontal spinogenesis plays a critical role in sustaining specific antidepressant behavioral effects and maintaining long-term behavioral remission. Depression-related behavior was associated with targeted, branch-specific elimination of postsynaptic dendritic spines on prefrontal projection neurons. Antidepressant-dose ketamine reversed these effects by selectively rescuing eliminated spines and restoring coordinated activity in multicellular ensembles that predict motivated escape behavior. Prefrontal spinogenesis was required for the long-term maintenance of antidepressant effects on motivated escape behavior but not for their initial induction.


Assuntos
Antidepressivos/farmacologia , Espinhas Dendríticas/efeitos dos fármacos , Transtorno Depressivo/fisiopatologia , Ketamina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Estresse Psicológico/fisiopatologia , Sinapses/efeitos dos fármacos , Animais , Antidepressivos/uso terapêutico , Corticosterona/farmacologia , Espinhas Dendríticas/patologia , Espinhas Dendríticas/fisiologia , Transtorno Depressivo/induzido quimicamente , Transtorno Depressivo/tratamento farmacológico , Modelos Animais de Doenças , Reação de Fuga/efeitos dos fármacos , Ketamina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Plasticidade Neuronal/efeitos dos fármacos , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia , Estresse Psicológico/induzido quimicamente , Sinapses/fisiologia
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