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1.
Neuroscience ; 476: 72-89, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34543675

RESUMO

Displaying a stress response to threatening stimuli is essential for survival. These reactions must be adjusted to be adaptive. Otherwise, even mental illnesses may develop. Describing the physiological stress response may contribute to distinguishing the abnormal responses that accompany the pathology, which may help to improve the development of both diagnoses and treatments. Recent advances have elucidated many of the processes and structures involved in stress response management; however, there is still much to unravel regarding this phenomenon. The main aim of the present research is to characterize the response of three brain areas deeply involved in the stress response (i.e., to an acute stressful experience). Specifically, the electrophysiological activity of the infralimbic division of the medial prefrontal cortex (IL), the basolateral nucleus of the amygdala (BLA), and the dorsal hippocampus (dHPC) was recorded after the infusion of 0.5 µl of corticosterone-releasing factor into the dorsal raphe nucleus (DRN), a procedure which has been validated as a paradigm to cause acute stress. This procedure induced a delayed reduction in slow waves in the three structures, and an increase in faster oscillations, such as those in theta, beta, and gamma bands. The mutual information at low theta frequencies between the BLA and the IL increased, and the delta and slow wave mutual information decreased. The low theta-mid gamma phase-amplitude coupling increased within BLA, as well as between BLA and IL. This electrical pattern may facilitate the activation of these structures, in response to the stressor, and memory consolidation.

2.
Brain Struct Funct ; 226(8): 2603-2616, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34363521

RESUMO

Ketamine has rapid and robust antidepressant effects. However, unwanted psychotomimetic effects limit its widespread use. Hence, several studies examined whether GluN2B-subunit selective NMDA antagonists would exhibit a better therapeutic profile. Although preclinical work has revealed some of the mechanisms of action of ketamine at cellular and molecular levels, the impact on brain circuitry is poorly understood. Several neuroimaging studies have examined the functional changes in the brain induced by acute administration of ketamine and Ro 25-6981 (a GluN2B-subunit selective antagonist), but the changes in the microstructure of gray and white matter have received less attention. Here, the effects of ketamine and Ro 25-6981 on gray and white matter integrity in male Sprague-Dawley rats were determined using diffusion-weighted magnetic resonance imaging (DWI). In addition, DWI-based structural brain networks were estimated and connectivity metrics were computed at the regional level. Immunohistochemical analyses were also performed to determine whether changes in myelin basic protein (MBP) and neurofilament heavy-chain protein (NF200) may underlie connectivity changes. In general, ketamine and Ro 25-6981 showed some opposite structural alterations, but both compounds coincided only in increasing the fractional anisotropy in infralimbic prefrontal cortex and dorsal raphe nucleus. These changes were associated with increments of NF200 in deep layers of the infralimbic cortex (together with increased MBP) and the dorsal raphe nucleus. Our results suggest that the synthesis of NF200 and MBP may contribute to the formation of new dendritic spines and myelination, respectively. We also suggest that the increase of fractional anisotropy of the infralimbic and dorsal raphe nucleus areas could represent a biomarker of a rapid antidepressant response.

3.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445375

RESUMO

Fast and sustained antidepressant effects of ketamine identified the mammalian target of rapamycin (mTOR) signaling pathway as the main modulator of its antidepressive effects. Thus, mTOR signaling has become integral for the preclinical evaluation of novel compounds to treat depression. However, causality between mTOR and depression has yet to be determined. To address this, we knocked down mTOR expression in mice using an acute intracerebral infusion of small interfering RNAs (siRNA) in the infralimbic (IL) or prelimbic (PrL) cortices of the medial prefrontal cortex (mPFC), and evaluated depressive- and anxious-like behaviors. mTOR knockdown in IL, but not PrL, cortex produced a robust depressive-like phenotype in mice, as assessed in the forced swimming test (FST) and the tail suspension test (TST). This phenotype was associated with significant reductions of mTOR mRNA and protein levels 48 h post-infusion. In parallel, decreased brain-derived neurotrophic factor (BDNF) expression was found bilaterally in both IL and PrL cortices along with a dysregulation of serotonin (5-HT) and glutamate (Glu) release in the dorsal raphe nucleus (DRN). Overall, our results demonstrate causality between mTOR expression in the IL cortex and depressive-like behaviors, but not in anxiety.


Assuntos
Depressão/psicologia , Córtex Pré-Frontal/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/genética , Depressão/metabolismo , Modelos Animais de Doenças , Núcleo Dorsal da Rafe/metabolismo , Técnicas de Silenciamento de Genes , Ácido Glutâmico/metabolismo , Elevação dos Membros Posteriores , Masculino , Camundongos , Serotonina/metabolismo , Natação
4.
Biochem Pharmacol ; 185: 114433, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33513342

RESUMO

Major Depression is a severe psychiatric condition with a still poorly understood etiology. In the last years, evidence supporting the neuroinflammatory hypothesis of depression has increased. In the current clinical scenario, in which the available treatments for depression is far from optimal, there is an urgent need to develop fast-acting drugs with fewer side effects. In this regard, recent pieces of evidence suggest that cannabidiol (CBD), the major non-psychotropic component of Cannabis sativa with anti-inflammatory properties, appears as a drug with antidepressant properties. In this work, CBD 30 mg/kg was administered systemically to mice 30 min before lipopolysaccharide (LPS; 0.83 mg/kg) administration as a neuroinflammatory model, and behavioral tests for depressive-, anhedonic- and anxious-like behavior were performed. NF-ĸB, IκBα and PPARγ levels were analyzed by western blot in nuclear and cytosolic fractions of cortical samples. IL-6 and TNFα levels were determined in plasma and prefrontal cortex using ELISA and qPCR techniques, respectively. The precursor tryptophan (TRP), and its metabolites kynurenine (KYN) and serotonin (5-HT) were measured in hippocampus and cortex by HPLC. The ratios KYN/TRP and KYN/5-HT were used to estimate indoleamine 2,3-dioxygenase (IDO) activity and the balance of both metabolic pathways, respectively. CBD reduced the immobility time in the tail suspension test and increased sucrose preference in the LPS model, without affecting locomotion and central activity in the open-field test. CBD diminished cortical NF-ĸB activation, IL-6 levels in plasma and brain, and the increased KYN/TRP and KYN/5-HT ratios in hippocampus and cortex in the LPS model. Our results demonstrate that CBD produced antidepressant-like effects in the LPS neuroinflammatory model, associated to a reduction in the kynurenine pathway activation, IL-6 levels and NF-ĸB activation. As CBD stands out as a promising antidepressant drug, more research is needed to completely understand its mechanisms of action in depression linked to inflammation.


Assuntos
Antidepressivos/uso terapêutico , Canabidiol/uso terapêutico , Depressão/tratamento farmacológico , Depressão/metabolismo , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Animais , Antidepressivos/farmacologia , Canabidiol/farmacologia , Depressão/induzido quimicamente , Elevação dos Membros Posteriores/efeitos adversos , Elevação dos Membros Posteriores/psicologia , Mediadores da Inflamação/antagonistas & inibidores , Masculino , Camundongos
5.
Biomolecules ; 10(6)2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32585886

RESUMO

N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP), dizocilpine (MK-801) and ketamine have long been considered a model of schizophrenia, both in animals and humans. However, ketamine has been recently approved for treatment-resistant depression, although with severe restrictions. Interestingly, the dosage in both conditions is similar, and positive symptoms of schizophrenia appear before antidepressant effects emerge. Here, we describe the temporal mechanisms implicated in schizophrenia-like and antidepressant-like effects of NMDA blockade in rats, and postulate that such effects may indicate that NMDA receptor antagonists induce similar mechanistic effects, and only the basal pre-drug state of the organism delimitates the overall outcome. Hence, blockade of NMDA receptors in depressive-like status can lead to amelioration or remission of symptoms, whereas healthy individuals develop psychotic symptoms and schizophrenia patients show an exacerbation of these symptoms after the administration of NMDA receptor antagonists.


Assuntos
Encéfalo/efeitos dos fármacos , Depressão/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/tratamento farmacológico , Animais , Encéfalo/metabolismo , Depressão/metabolismo , Maleato de Dizocilpina/farmacologia , Humanos , Ketamina/farmacologia , Fenciclidina/farmacologia , Esquizofrenia/metabolismo
6.
Mol Neurobiol ; 57(8): 3498-3507, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32535760

RESUMO

Conventional antidepressant drugs elevate the availability of monoamine neurotransmitters. However, these pharmacological therapies have limited efficacy and a slow onset of action as main limitations. New glutamatergic drugs such as ketamine have shown promise as a rapid-acting antidepressant drugs although with adverse effects. The mechanism of action of ketamine is hypothesized to involve a dis-inhibition of cortical pyramidal neurons produced by an stimulation of AMPA receptors by glutamate. In this context, low-impact positive allosteric modulators of the AMPA receptors (a.k.a. ampakines) have been regarded as potential antidepressant drugs. Here, we have examined the behavioral, biochemical, and molecular effects of a low-impact ampakine, CX717. Our results show that CX717 has a rapid (30 min) but short-lasting (up to 24 h) antidepressant-like effect in the forced swim test. Intra-cortical infusion of CX717 increases the efflux of noradrenaline, dopamine, and serotonin, but not glutamate. However, systemic CX717 does not alter these neurotransmitters. CX717 also produced a rapid (up to 1 h) increase of brain-derived neurotrophic factor (BDNF) and a more sustained (up to 6 h) increase of p11. Overall, CX717 appears to possess a rapid but not sustained antidepressant action possibly caused by rapid increases of BDNF and p11.


Assuntos
Antidepressivos/farmacologia , Isoxazóis/farmacologia , Receptores de AMPA/efeitos dos fármacos , Receptores de AMPA/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Peptídeos Penetradores de Células/metabolismo , Depressão/tratamento farmacológico , Ácido Glutâmico/farmacologia , Masculino , Ratos Sprague-Dawley , Serotonina/farmacologia
7.
Mol Neurobiol ; 57(3): 1704-1715, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31823197

RESUMO

We previously reported that the inactivation (cKO) or the stabilization (cST) of ß-catenin in cells expressing the astrocyte-specific glutamate aspartate transporter (GLAST) is associated with the vulnerability or resilience to exhibit anxious/depressive-like behaviors, respectively, and to changes in hippocampal proliferation. Here, we used these cKO and cST ß-catenin mice to study the serotonergic system functionality associated with their behavioral/molecular phenotype. The activity of 5-HT1A receptors was assessed by (+)-8-OH-DPAT-induced hypothermia and [35S]GTPγS binding autoradiography. The animals' response to acute stress and the levels of extracellular serotonin (5-HT) in the medial prefrontal cortex (mPFC) were also assessed. cKO mice presented higher 5-HT1A autoreceptor functionality, lower 5-HT1A heteroreceptor functionality, and a decrease in extracellular 5-HT levels in the mPFC. These neurochemical changes were accompanied with a blunted physiological response to stress-induced hyperthermia. In contrast, cST mice showed a reduced 5-HT1A autoreceptor functionality and higher extracellular 5-HT levels in the mPFC after fluoxetine administration. Moreover, cST mice subjected to chronic corticosterone administration did not show a blunted response to fluoxetine. Our findings suggest the existence of a link between ß-catenin levels and 5-HT1A receptor functionality, which may be relevant to understand the neurobiological bases underlying the vulnerability or resilience to stress-related disorders.


Assuntos
Ansiedade/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Serotonina/metabolismo , beta Catenina/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Corticosterona/metabolismo , Depressão/metabolismo , Hipocampo/metabolismo , Masculino , Camundongos , Córtex Pré-Frontal/metabolismo
8.
ACS Chem Neurosci ; 10(7): 3318-3326, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31244055

RESUMO

Depression is a chronic and debilitating illness that interferes severely with many human behaviors, and is the leading cause of disability in the world. There is data suggesting that deficits in serotonin neurotransmission can contribute to the development of depression. Indeed, >90% of prescribed antidepressant drugs act by increasing serotonergic transmission at the synapse. However, this increase is offset by a negative feedback operating at the level of the cell body of the serotonin neurons in the raphe nuclei. In the present work, we demonstrate: first, the intracortical infusion of ketamine induced an antidepressant-like effect in the forced swim test, comparable to that produced by systemic ketamine; second, systemic and intracortical ketamine increased serotonin and noradrenaline efflux in the prefrontal cortex, but not in the dorsal raphe nucleus; third, systemic and intracortical administration of ketamine increased the efflux of glutamate in the prefrontal cortex and dorsal raphe nucleus; fourth, systemic ketamine did not alter the functionality of 5-HT1A receptors in the dorsal raphe nucleus. Taken together, these findings suggest that the antidepressant-like effects of ketamine are caused by the stimulation of the prefrontal projection to the dorsal raphe nucleus and locus coeruleus caused by an elevated glutamate in the medial prefrontal cortex, which would stimulate release of serotonin and noradrenaline in the same area. The impact of both monoamines in the antidepressant response to ketamine seems to have different time frames.


Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Núcleo Dorsal da Rafe/efeitos dos fármacos , Ketamina/farmacologia , Norepinefrina/metabolismo , Neurônios Serotoninérgicos/efeitos dos fármacos , Serotonina/metabolismo , Animais , Antidepressivos/uso terapêutico , Depressão/metabolismo , Núcleo Dorsal da Rafe/metabolismo , Ácido Glutâmico/metabolismo , Ketamina/uso terapêutico , Masculino , Atividade Motora/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/metabolismo , Neurônios Serotoninérgicos/metabolismo
9.
Transl Psychiatry ; 8(1): 84, 2018 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-29666360

RESUMO

In a previous study we found that the preferring GluN2A receptor antagonist, NVP-AAM077, elicited rapid antidepressant-like effects in the forced swim test that was related to the release of glutamate and serotonin in the medial prefrontal cortex. In the present work we sought to examine the duration of this behavioral effect as well as the molecular readouts involved. Our results showed that NVP-AAM077 reduced the immobility in the forced swim test 30 min and 24 h after its administration. However, this effect waned 7 days later. The rapid antidepressant-like response seems to be associated with increases in the GluA1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, mammalian target of rapamycin (mTOR) signaling, glia markers such as glial fibrillary acidic protein (GFAP) and excitatory amino acid transporter 1 (EAAT1), and a rapid mobilization of intracellular stores of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex.


Assuntos
Antidepressivos/administração & dosagem , Depressão/tratamento farmacológico , Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Quinoxalinas/administração & dosagem , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Masculino , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Ratos Sprague-Dawley , Receptores de AMPA , Transdução de Sinais , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Serina-Treonina Quinases TOR/metabolismo
10.
J Comp Neurol ; 526(8): 1403-1416, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29473165

RESUMO

The stress system coordinates the adaptive reactions of the organism to stressors. Therefore, dysfunctions in this circuit may correlate to anxiety-related disorders, including depression. Comprehending the dynamics of this network may lead to a better understanding of the mechanisms that underlie these diseases. The central nucleus of the amygdala (CeA) activates the hypothalamic-pituitary-adrenal axis and brainstem nodes by triggering endocrine, autonomic and behavioral stress responses. The medial prefrontal cortex plays a significant role in regulating reactions to stressors, and is specifically important for limiting fear responses. Brain oscillations reflect neural systems activity. Synchronous neuronal assemblies facilitate communication and synaptic plasticity, mechanisms that cooperatively support the temporal representation and long-term consolidation of information. The purpose of this article was to delve into the interactions between these structures in stress contexts by evaluating changes in oscillatory activity. We particularly analyzed the local field potential in the infralimbic region of the medial prefrontal cortex (IL) in urethane-anesthetized rats after the electrical activation of the central nucleus of the amygdala by mimicking firing rates induced by acute stress. Electrical CeA activation induced a delayed, but significant, change in the IL, with prominent slow waves accompanied by an increase in the theta and gamma activities, and spindles. The phase-amplitude coupling of both slow waves and theta oscillations significantly increased with faster oscillations, including theta-gamma coupling and the nesting of spindles, theta and gamma oscillations in the slow wave cycle. These results are further discussed in neural processing terms of the stress response and memory formation.


Assuntos
Vias Aferentes/fisiologia , Tonsila do Cerebelo/fisiologia , Córtex Cerebral/citologia , Estimulação Elétrica/métodos , Potenciais Evocados/fisiologia , Neurônios/fisiologia , Animais , Feminino , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
11.
Physiol Rep ; 4(14)2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27449812

RESUMO

Deep brain stimulation (DBS) is a new investigational therapy that has generated positive results in refractory depression. Although the neurochemical and behavioral effects of DBS have been examined, less attention has been paid to the influence of DBS on the network dynamics between different brain areas, which could contribute to its therapeutic effects. Herein, we set out to identify the effects of 1 h DBS in the infralimbic cortex (IL) on the oscillatory network dynamics between hippocampus and basolateral amygdala (BLA), two regions implicated in depression and its treatment. Urethane-anesthetized rats with bilaterally implanted electrodes in the IL were exposed to 1 h constant stimulation of 130 Hz of frequency, 60 µA of constant current intensity and biphasic pulse width of 80 µsec. After a period of baseline recording, local field potentials (LFP) were recorded with formvar-insulated stainless steel electrodes. DBS of the IL increased the power of slow wave (SW, <1.5 Hz) and theta (3-12 Hz) frequencies in the hippocampus and BLA Furthermore, IL DBS caused a precise coupling in different frequency bands between both brain structures. The increases in SW band synchronization in hippocampus and BLA after DBS suggest that these changes may be important for the improvement of depressive behavior. In addition, the augmentation in theta synchrony might contribute to improvement in emotional and cognitive processes.


Assuntos
Tonsila do Cerebelo/fisiologia , Ondas Encefálicas , Estimulação Encefálica Profunda , Eletroencefalografia , Hipocampo/fisiologia , Córtex Pré-Frontal/fisiologia , Animais , Comportamento Animal , Masculino , Vias Neurais/fisiologia , Ratos Wistar , Processamento de Sinais Assistido por Computador , Fatores de Tempo
12.
Neuropharmacology ; 108: 91-102, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27108934

RESUMO

Deep brain stimulation (DBS) is a treatment that has shown some efficacy in treatment-resistant depression. In particular, DBS of the subcallosal cingulate gyrus (Brodmann's area 25, Cg25) has been successfully applied to treat refractory depression. In the rat, we have demonstrated that DBS applied to infralimbic (IL) cortex elevates the levels of glutamate and monoamines in the prefrontal cortex, and requires the stimulation of cortical α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors for its antidepressant-like effects. However, the molecular targets of IL DBS are not fully known. To gain insight into these pathways, we have investigated whether IL DBS is able to reverse the behavioral, biochemical and molecular changes exhibited by the olfactory bulbectomized (OBX) rat. Our results revealed that 1 h IL DBS diminished hyperlocomotion, hyperemotionality and anhedonia, and increased social interaction shown by the OBX rats. Further, IL DBS increased prefrontal efflux of glutamate and serotonin in both sham-operated and OBX rats. With regard to molecular targets, IL DBS increases the synthesis of brain-derived neurotrophic factor (BDNF) and the GluA1 AMPA receptor subunit, and stimulates the Akt/mammalian target of rapamycin (mTOR) as well as the AMPA receptor/c-AMP response element binding (CREB) pathways. Temsirolimus, a known in vivo mTOR blocker, suppressed the antidepressant-like effect of IL DBS in naïve rats in the forced swim test, thus demonstrating for the first time that mTOR signaling is required for the antidepressant-like effects of IL DBS, which is in line with the antidepressant response of other rapid-acting antidepressant drugs.


Assuntos
Estimulação Encefálica Profunda/métodos , Depressão/metabolismo , Relações Interpessoais , Córtex Pré-Frontal/química , Córtex Pré-Frontal/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Depressão/cirurgia , Masculino , Bulbo Olfatório/química , Bulbo Olfatório/metabolismo , Bulbo Olfatório/cirurgia , Córtex Pré-Frontal/cirurgia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar
13.
Neuropharmacology ; 103: 16-26, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26711860

RESUMO

Cannabidiol (CBD), the main non-psychotomimetic component of marihuana, exhibits anxiolytic-like properties in many behavioural tests, although its potential for treating major depression has been poorly explored. Moreover, the mechanism of action of CBD remains unclear. Herein, we have evaluated the effects of CBD following acute and chronic administration in the olfactory bulbectomy mouse model of depression (OBX), and investigated the underlying mechanism. For this purpose, we conducted behavioural (open field and sucrose preference tests) and neurochemical (microdialysis and autoradiography of 5-HT1A receptor functionality) studies following treatment with CBD. We also assayed the pharmacological antagonism of the effects of CBD to dissect out the mechanism of action. Our results demonstrate that CBD exerts fast and maintained antidepressant-like effects as evidenced by the reversal of the OBX-induced hyperactivity and anhedonia. In vivo microdialysis revealed that the administration of CBD significantly enhanced serotonin and glutamate levels in vmPFCx in a different manner depending on the emotional state and the duration of the treatment. The potentiating effect upon neurotransmitters levels occurring immediately after the first injection of CBD might underlie the fast antidepressant-like actions in OBX mice. Both antidepressant-like effect and enhanced cortical 5-HT/glutamate neurotransmission induced by CBD were prevented by 5-HT1A receptor blockade. Moreover, adaptive changes in pre- and post-synaptic 5-HT1A receptor functionality were also found after chronic CBD. In conclusion, our findings indicate that CBD could represent a novel fast antidepressant drug, via enhancing both serotonergic and glutamate cortical signalling through a 5-HT1A receptor-dependent mechanism.


Assuntos
Ansiolíticos/administração & dosagem , Antidepressivos/administração & dosagem , Canabidiol/administração & dosagem , Transtorno Depressivo/metabolismo , Ácido Glutâmico/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Serotonina/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Bulbo Olfatório/cirurgia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Transmissão Sináptica/efeitos dos fármacos
14.
Cereb Cortex ; 26(6): 2778-2789, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26088969

RESUMO

Although deep brain stimulation (DBS) has been used with success in treatment-resistant depression, little is known about its mechanism of action. We examined the antidepressant-like activity of short (1 h) DBS applied to the infralimbic prefrontal cortex in the forced swim test (FST) and the novelty-suppressed feeding test (NSFT). We also used in vivo microdialysis to evaluate the release of glutamate, γ-aminobutyric acid, serotonin, dopamine, and noradrenaline in the prefrontal cortex and c-Fos immunohistochemistry to determine the brain regions activated by DBS. One hour of DBS of the infralimbic prefrontal cortex has antidepressant-like effects in FST and NSFT, and increases prefrontal efflux of glutamate, which would activate AMPA receptors (AMPARs). This effect is specific of the infralimbic area since it is not observed after DBS of the prelimbic subregion. The activation of prefrontal AMPARs would result in a stimulation of prefrontal output to the brainstem, thus increasing serotonin, dopamine, and noradrenaline in the prefrontal cortex. Further, the activation of prefrontal AMPARs is necessary and sufficient condition for the antidepressant response of 1 h DBS.


Assuntos
Estimulação Encefálica Profunda/métodos , Transtorno Depressivo/metabolismo , Transtorno Depressivo/terapia , Córtex Pré-Frontal/metabolismo , Receptores de AMPA/metabolismo , Animais , Transtorno Depressivo/patologia , Modelos Animais de Doenças , Dopamina/metabolismo , Ácido Glutâmico/metabolismo , Imuno-Histoquímica , Masculino , Microdiálise , Norepinefrina/metabolismo , Córtex Pré-Frontal/patologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar , Serotonina/metabolismo , Ácido gama-Aminobutírico/metabolismo
16.
Neuropsychopharmacology ; 39(11): 2673-80, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24871546

RESUMO

Paradoxically, N-methyl-D-aspartate (NMDA) receptor antagonists are used to model certain aspects of schizophrenia as well as to treat refractory depression. However, the role of different subunits of the NMDA receptor in both conditions is poorly understood. Here we used biochemical and behavioral readouts to examine the in vivo prefrontal efflux of serotonin and glutamate as well as the stereotypical behavior and the antidepressant-like activity in the forced swim test elicited by antagonists selective for the GluN2A (NVP-AAM077) and GluN2B (Ro 25-6981) subunits. The effects of the non-subunit selective antagonist, MK-801; were also studied for comparison. The administration of MK-801 dose dependently increased the prefrontal efflux of serotonin and glutamate and markedly increased the stereotypy scores. NVP-AAM077 also increased the efflux of serotonin and glutamate, but without the induction of stereotypies. In contrast, Ro 25-6981 did not change any of the biochemical and behavioral parameters tested. Interestingly, the administration of NVP-AAM077 and Ro 25-6981 alone elicited antidepressant-like activity in the forced swim test, in contrast to the combination of both compounds that evoked marked stereotypies. Our interpretation of the results is that both GluN2A and GluN2B subunits are needed to induce stereotypies, which might be suggestive of potential psychotomimetic effects in humans, but the antagonism of only one of these subunits is sufficient to evoke an antidepressant response. We also propose that GluN2A receptor antagonists could have potential antidepressant activity in the absence of potential psychotomimetic effects.


Assuntos
Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia , Animais , Antidepressivos/farmacologia , Transtorno Depressivo Resistente a Tratamento/fisiopatologia , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Ácido Glutâmico/metabolismo , Masculino , Fenóis/farmacologia , Piperidinas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Quinoxalinas/farmacologia , Ratos Wistar , Esquizofrenia/fisiopatologia , Serotonina/metabolismo , Comportamento Estereotipado/efeitos dos fármacos , Comportamento Estereotipado/fisiologia
17.
CNS Neurol Disord Drug Targets ; 13(1): 104-11, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24040788

RESUMO

Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists can produce positive and negative symptomatology as well as impairment of cognitive function that closely resemble those present in schizophrenia. In rats, these drugs induce a behavioral syndrome (characterized by hyperlocomotion and stereotypies), an enhanced glutamatergic transmission in the medial prefrontal cortex, and damage to retrosplenial cortical neurons in adult rats, which was measured as the induction of the stress protein 72/73 kDa heat shock protein (Hsp72/73). In the present work, we have examined the existence of possible differences among different antipsychotic drugs in their capacity to block immunolabeling of Hsp72/73 in the retrosplenial cortex of the rat induced by the potent NMDA receptor antagonist, MK- 801. In addition, the effects of selective monoaminergic agents were also studied to delineate the particular receptors responsible for the actions of antipsychotic drugs. Pretreatment with clozapine, chlorpromazine, olanzapine, ziprasidone--and to a lesser extent haloperidol-reduced the formation of Hsp72/73 protein in the rat retrosplenial cortex after the administration of MK-801. In addition, antagonism at dopamine D2 (raclopride), 5-HT2 (M100907) and α1- adrenoceptors (prazosin) as well as agonism at 5-HT1A receptors (BAY x 3702) also diminished the MK-801-induced number of cells labeled with Hsp72/73. Each of these effects may contribute to antipsychotic action. The results suggest that the efficacy of atypical antipsychotic drugs in the clinic may result from a combined effect on 5-HT2, 5-HT1A and α1-adrenergic receptors added to the classical dopamine D2 receptor antagonism.


Assuntos
Antipsicóticos/farmacologia , Encéfalo/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Proteínas de Choque Térmico HSP72/metabolismo , Receptores de Amina Biogênica/metabolismo , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Contagem de Células , Interações Medicamentosas , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Receptores de Dopamina D2/metabolismo
18.
Neuropharmacology ; 79: 49-58, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24211653

RESUMO

The prefrontal cortex (PFC) is involved in higher brain functions altered in schizophrenia. Classical antipsychotic drugs modulate information processing in cortico-limbic circuits via dopamine D2 receptor blockade in nucleus accumbens (NAc) whereas atypical antipsychotic drugs preferentially target cortical serotonin (5-HT) receptors. The brain networks involved in the therapeutic action of atypical drugs are not fully understood. Previous work indicated that medial PFC (mPFC) pyramidal neurons projecting to ventral tegmental area express 5-HT2A receptors suggesting that atypical antipsychotic drugs modulate dopaminergic activity distally, via 5-HT2A receptor (5-HT2A-R) blockade in PFC. Since the mPFC also projects heavily to NAc, we examined whether NAc-projecting pyramidal neurons also express 5-HT2A-R. Using a combination of retrograde tracing experiments and in situ hybridization we report that a substantial proportion of mPFC-NAc pyramidal neurons in rat brain express 5-HT2A-R mRNA in a layer- and area-specific manner (up to 68% in layer V of contralateral cingulate). The functional relevance of 5-HT2A-R to modulate mPFC-NAc projections was examined in dual-probe microdialysis experiments. The application of the preferential 5-HT2A-R agonist DOI into mPFC enhanced glutamate release locally (+66 ± 18%) and in NAc (+74 ± 12%) indicating that cortical 5-HT2A-R activation augments glutamatergic transmission in NAc. Since NAc integrates glutamatergic and dopaminergic inputs, blockade of 5-HT2A-R by atypical drugs may reduce cortical excitatory inputs onto GABAergic neurons of NAc, adding to dopamine D2 receptor blockade. Together with previous observations, the present results suggest that atypical antipsychotic drugs may control the activity of the mesolimbic pathway at cell body and terminal level.


Assuntos
Antipsicóticos/farmacologia , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , Células Piramidais/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Anfetaminas/farmacologia , Animais , Ácido Glutâmico/metabolismo , Hibridização In Situ , Masculino , Microdiálise , Vias Neurais/anatomia & histologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Técnicas de Rastreamento Neuroanatômico , Núcleo Accumbens/anatomia & histologia , Núcleo Accumbens/efeitos dos fármacos , Córtex Pré-Frontal/anatomia & histologia , Córtex Pré-Frontal/efeitos dos fármacos , Células Piramidais/citologia , Células Piramidais/efeitos dos fármacos , RNA Mensageiro , Ratos , Ratos Wistar , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia
19.
Int J Neuropsychopharmacol ; 15(7): 945-56, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21733285

RESUMO

Previous studies have shown that systemic, but not unilateral intra-prefrontal cortex administration of non-competitive NMDA antagonists, increased prefrontal activity, the cortical efflux of serotonin, and induced stereotypies. In this work we used in-vivo microdialysis and immunohistochemistry to test the hypothesis as to whether MK-801 and ketamine need to act on both prefrontal cortices to reproduce these neurochemical and behavioural changes. Dialysis probes were implanted in the medial prefrontal cortex, and extracellular serotonin as well as behavioural stereotypies was measured after systemic administration of MK-801 and ketamine (1 mg/kg and 25 mg/kg, respectively), and unilateral and bilateral perfusion of both drugs (300 µm and 3 mm, respectively). Additionally, the prefrontal (glutamatergic) level of activity was measured using c-Fos immunohistochemistry. Systemic and bilateral (but not unilateral) prefrontal administration of MK-801 and ketamine increased serotonin efflux whereas only systemic administration of both drugs produced hyperlocomotion and stereotypies. The unilateral perfusion of 1 µm tetrodotoxin in the medial prefrontal cortex reduced increases of serotonin in both hemispheres, the expression of c-Fos in the contralateral side, and stereotypy scores after systemic NMDA antagonists. Our results support the hypothesis that a bilateral impairment of cortical inhibition in the medial prefrontal cortex is needed for non-competitive NMDA antagonists to induce the state of pyramidal cell hyperactivity and concurrent efflux of serotonin. Furthermore, hyperlocomotion and stereotypies produced by MK-801 and ketamine do not appear to result from changes in the activity of prefrontal cortex although this structure exerts some control over these behaviours.


Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Lateralidade Funcional/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Análise de Variância , Anestésicos Locais/farmacologia , Animais , Maleato de Dizocilpina/farmacologia , Vias de Administração de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Ketamina/farmacologia , Masculino , Microdiálise , Vias Neurais/fisiologia , Córtex Pré-Frontal/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/metabolismo , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Serotonina/metabolismo , Comportamento Estereotipado/efeitos dos fármacos , Tetrodotoxina/farmacologia , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo
20.
Schizophr Bull ; 38(1): 9-14, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21965469

RESUMO

Several genetic, neurodevelopmental, and pharmacological animal models of schizophrenia have been established. This short review examines the validity of one of the most used pharmacological model of the illness, ie, the acute administration of N-methyl-D-aspartate (NMDA) receptor antagonists in rodents. In some cases, data on chronic or prenatal NMDA receptor antagonist exposure have been introduced for comparison. The face validity of acute NMDA receptor blockade is granted inasmuch as hyperlocomotion and stereotypies induced by phencyclidine, ketamine, and MK-801 are regarded as a surrogate for the positive symptoms of schizophrenia. In addition, the loss of parvalbumin-containing cells (which is one of the most compelling finding in postmortem schizophrenia brain) following NMDA receptor blockade adds construct validity to this model. However, the lack of changes in glutamic acid decarboxylase (GAD(67)) is at variance with human studies. It is possible that changes in GAD(67) are more reflective of the neurodevelopmental condition of schizophrenia. Finally, the model also has predictive validity, in that its behavioral and transmitter activation in rodents are responsive to antipsychotic treatment. Overall, although not devoid of drawbacks, the acute administration of NMDA receptor antagonists can be considered as a good model of schizophrenia bearing a satisfactory degree of validity.


Assuntos
Modelos Animais de Doenças , Ketamina/farmacologia , Fenciclidina/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia , Esquizofrenia/fisiopatologia , Animais , Corpo Caloso/fisiopatologia , Dopamina/farmacologia , Ácido Glutâmico/farmacologia , Humanos , Parvalbuminas/farmacologia , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Roedores , Serotonina/farmacologia
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