RESUMEN
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.
Asunto(s)
Depresión/psicología , Corteza Prefrontal/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Depresión/genética , Depresión/metabolismo , Modelos Animales de Enfermedad , Núcleo Dorsal del Rafe/metabolismo , Técnicas de Silenciamiento del Gen , Ácido Glutámico/metabolismo , Suspensión Trasera , Masculino , Ratones , Serotonina/metabolismo , NataciónRESUMEN
TaqIA is a polymorphism associated with addictions and dopamine-related traits. It is located in the ankyrin repeat and kinase domain containing 1 gene (ANKK1) nearby the gene for the dopamine D2 receptor (D2R). Since ANKK1 function is unknown, TaqIA-associated traits have been explained only by differences in D2R. Here we report ANKK1 studies in mouse and human brain using quantitative real-time PCR, Western blot, immunohistochemistry, and flow cytometry. ANKK1 mRNA and protein isoforms vary along neurodevelopment in the human and mouse brain. In mouse adult brain ANKK1 is located in astrocytes, nuclei of postmitotic neurons and neural precursors from neurogenic niches. In both embryos and adults, nuclei of neural precursors show significant variation of ANKK1 intensity. We demonstrate a correlation between ANKK1 and the cell cycle. Cell synchronization experiments showed a significant increment of ANKK1-kinase in mitotic cells while ANKK1-kinase overexpression affects G1 and M phase that were found to be modulated by ANKK1 alleles and apomorphine treatment. Furthermore, during embryonic neurogenesis ANKK1 was expressed in slow-dividing neuroblasts and rapidly dividing precursors which are mitotic cells. These results suggest a role of ANKK1 during the cell cycle in neural precursors thus providing biological support to brain structure involvement in the TaqIA-associated phenotypes.
Asunto(s)
Encéfalo/metabolismo , Ciclo Celular/fisiología , Regulación del Desarrollo de la Expresión Génica/genética , Células-Madre Neurales/fisiología , Proteínas Serina-Treonina Quinasas/metabolismo , Adolescente , Factores de Edad , Animales , Animales Recién Nacidos , Encéfalo/embriología , Encéfalo/crecimiento & desarrollo , Diferenciación Celular/fisiología , Línea Celular Tumoral , Embrión de Mamíferos , Feto , Edad Gestacional , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Lactante , Ratones , Persona de Mediana Edad , Neurogénesis/fisiología , Proteínas Serina-Treonina Quinasas/genética , ARN Mensajero/metabolismo , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismoRESUMEN
There is strong biochemical, pharmacological and genetic evidence for the involvement of the endocannabinoid system (ECS) in alcohol dependence. However, the majority of studies have been performed in animal models. The aim of the present study was to assess the state of the CB1 receptor, the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and the extracellular signal-regulated kinase (ERK) and cyclic-AMP response element-binding protein (CREB) in the post-mortem prefrontal cortex of alcoholic subjects. Experiments were performed in samples from 44 subjects classified in four experimental groups: (1) non-suicidal alcoholic subjects (n = 11); (2) suicidal alcoholic subjects (n = 11); (3) non-alcoholic suicide victims (n = 11); and (4) control subjects (n = 11). We did not observe statistically significant differences in CB1 mRNA relative expression among the four experimental groups. Conversely, our results showed an increase in CB1 receptor protein expression in the prefrontal cortex of the suicidal alcoholic group (127.2 ± 7.3%), with no changes in functionality with regard to either G protein activation or the inhibition of adenylyl cyclase. In parallel, alcoholic subjects presented lower levels of MAGL activity, regardless of the cause of death. A significant decrease in the active form of ERK and CREB levels was also observed in both alcoholic groups. Taken together, our data are consistent with a role for the ECS in the neurobiological mechanisms underlying alcoholism. Moreover, the alterations reported here should be of great interest for the therapeutic treatment of this chronic psychiatric disease.
Asunto(s)
Alcoholismo/enzimología , Endocannabinoides/fisiología , Corteza Prefrontal/enzimología , Amidohidrolasas/metabolismo , Análisis de Varianza , Proteína de Unión a CREB/metabolismo , Cadáver , Estudios de Casos y Controles , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monoacilglicerol Lipasas/metabolismo , ARN Mensajero/metabolismo , Receptor Cannabinoide CB1/metabolismo , Transducción de Señal , SuicidioRESUMEN
Down syndrome (DS) is associated with neurological complications, including cognitive deficits that lead to impairment in intellectual functioning. Increased GABA-mediated inhibition has been proposed as a mechanism underlying deficient cognition in the Ts65Dn (TS) mouse model of DS. We show that chronic treatment of these mice with RO4938581 (3-bromo-10-(difluoromethyl)-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]diazepine), a selective GABA(A) α5 negative allosteric modulator (NAM), rescued their deficits in spatial learning and memory, hippocampal synaptic plasticity, and adult neurogenesis. We also show that RO4938581 normalized the high density of GABAergic synapse markers in the molecular layer of the hippocampus of TS mice. In addition, RO4938581 treatment suppressed the hyperactivity observed in TS mice without inducing anxiety or altering their motor abilities. These data demonstrate that reducing GABAergic inhibition with RO4938581 can reverse functional and neuromorphological deficits of TS mice by facilitating brain plasticity and support the potential therapeutic use of selective GABA(A) α5 NAMs to treat cognitive dysfunction in DS.
Asunto(s)
Síndrome de Down/complicaciones , Síndrome de Down/patología , Hipocampo/patología , Discapacidades para el Aprendizaje/tratamiento farmacológico , Neuronas/fisiología , Receptores de GABA-A/metabolismo , Estimulación Acústica , Análisis de Varianza , Animales , Benzodiazepinas/farmacología , Benzodiazepinas/uso terapéutico , Biofisica , Proteínas Portadoras/metabolismo , Recuento de Células , Proliferación Celular/efectos de los fármacos , Señales (Psicología) , Modelos Animales de Enfermedad , Síndrome de Down/tratamiento farmacológico , Estimulación Eléctrica , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/genética , Conducta Exploratoria/efectos de los fármacos , Moduladores del GABA/farmacología , Moduladores del GABA/uso terapéutico , Glutamato Descarboxilasa/metabolismo , Hipocampo/efectos de los fármacos , Hipercinesia/tratamiento farmacológico , Hipercinesia/etiología , Imidazoles/farmacología , Imidazoles/uso terapéutico , Antígeno Ki-67 , Discapacidades para el Aprendizaje/etiología , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/genética , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neurogénesis/efectos de los fármacos , Neurogénesis/genética , Neuronas/efectos de los fármacos , Unión Proteica/efectos de los fármacos , Unión Proteica/genética , Desempeño Psicomotor/efectos de los fármacos , Tiempo de Reacción/efectos de los fármacos , Reflejo/efectos de los fármacos , Reflejo/genética , Reflejo de Sobresalto/efectos de los fármacos , Prueba de Desempeño de Rotación con Aceleración Constante , Convulsiones/etiología , Filtrado Sensorial/efectos de los fármacos , Tritio/farmacocinética , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/metabolismoRESUMEN
The olfactory bulbectomized (OB) rat, an animal model of chronic depression with comorbid anxiety, exhibits a profound dysregulation of the brain serotonergic signalling, a neurotransmission system involved in pain transmission and modulation. We here report an increased nociceptive response of OB rats in the tail flick test which is reverted after chronic, but not acute, administration of fluoxetine. Autoradiographic studies demonstrated down-regulation of 5-HT transporters ([(3)H]citalopram binding) and decreased functionality of 5-HT1A receptors (8-OH-DPAT-stimulated [(35)S]GTPγS binding) in the dorsal horn of the lumbar spinal cord in OB rats. Acute administration of fluoxetine (5-40 mg/kg i.p.) did not modify tail flick latencies in OB rats. However, chronic fluoxetine (10 mg/kg/day s.c., 14 days; osmotic minipumps) progressively attenuated OB-associated thermal hyperalgesia, and a total normalization of the nociceptive response was achieved at the end of the treatment with the antidepressant. In these animals, autoradiographic studies revealed further down-regulation of 5-HT transporters and normalization in the functionality of 5-HT1A receptors on the spinal cord. On the other hand, acute morphine (0.5-10 mg/kg s.c.) produced a similar analgesic effect in OB and sham and OB rats, and no changes were detected in the density ([(3)H]DAMGO binding) and functionality (DAMGO-stimulated [(35)S]GTPγS binding) of spinal µ-opioid receptors in OB rats before and after chronic fluoxetine. Our findings demonstrate the participation of the spinal serotonergic system in the increased thermal nociception exhibited by the OB rat and the antinociceptive effect of chronic fluoxetine in this animal model of depression.
Asunto(s)
Depresión/complicaciones , Depresión/patología , Hiperalgesia/etiología , Serotonina/metabolismo , Médula Espinal/metabolismo , Animales , Antidepresivos/uso terapéutico , Autorradiografía , Depresión/tratamiento farmacológico , Modelos Animales de Enfermedad , Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacocinética , Conducta Exploratoria/fisiología , Guanosina 5'-O-(3-Tiotrifosfato)/farmacocinética , Hiperalgesia/tratamiento farmacológico , Masculino , Morfina/uso terapéutico , Neurotransmisores/farmacocinética , Bulbo Olfatorio/lesiones , Bulbo Olfatorio/cirugía , Dimensión del Dolor , Radiografía , Radioisótopos/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1A/metabolismo , Receptores Opioides mu/metabolismo , Serotoninérgicos/farmacocinética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Médula Espinal/diagnóstico por imagen , Médula Espinal/efectos de los fármacosRESUMEN
A wide variety of microorganisms has previously been identified as causes of brain infection. Among them, Listeria monocytogenes has a particular tropism for the central nervous system. To gain knowledge about the immune response elicited by L. monocytogenes in the brain, we used a rat ex vivo organotypic nervous system culture as a model for Listeria infection. Scanning electron microscopy (SEM) revealed that activated microglial cells showing a typical amoeboid morphology are quickly recruited to the surface of the explants after the infection. After bacterial engulfment, these cells appear to act as Trojan horses, releasing the engulfed bacteria inside the brain tissue. We describe cycles of microglial phagocytosis, necrotic cell death and the subsequent removal of cell debris for the first time. Furthermore, we used this ex vivo model to assess the expression profiles of immune relevant genes up to 24 h postinfection by means of q-PCR-arrays, finding that a number of inflammation-promoting genes are upregulated. Shortly after infection by L. monocytogenes, upregulated genes were those that encoded molecules involved in Th1 responses, being the Ccl2 chemokine and members of the interleukin1-ß family the most abundant immunomodulatory signals expressed. After 5 h of infection, L. monocytogenes caused a substantial increase in the expression of TLR1 and TLR2 genes, as well as in several downstream genes of the TLR signaling pathways.
Asunto(s)
Encefalopatías/microbiología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/inmunología , Listeria monocytogenes/genética , Listeriosis/genética , Listeriosis/patología , Microglía/microbiología , Microglía/patología , Animales , Animales Recién Nacidos , Encefalopatías/inmunología , Encefalopatías/patología , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Listeria monocytogenes/crecimiento & desarrollo , Listeria monocytogenes/inmunología , Listeriosis/inmunología , Microglía/ultraestructura , Microscopía Electrónica de Rastreo , Técnicas de Cultivo de Órganos , Ratas , Ratas Sprague-DawleyRESUMEN
It is widely accepted that changes underlying depression and antidepressant-like effects involve not only alterations in the levels of neurotransmitters as monoamines and their receptors in the brain, but also structural and functional changes far beyond. During the last two decades, emerging theories are providing new explanations about the neurobiology of depression and the mechanism of action of antidepressant strategies based on cellular changes at the CNS level. The neurotrophic/plasticity hypothesis of depression, proposed more than a decade ago, is now supported by multiple basic and clinical studies focused on the role of intracellular-signalling cascades that govern neural proliferation and plasticity. Herein, we review the state-of-the-art of the changes in these signalling pathways which appear to underlie both depressive disorders and antidepressant actions. We will especially focus on the hippocampal cellularity and plasticity modulation by serotonin, trophic factors as brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) through intracellular signalling pathways-cAMP, Wnt/ ß -catenin, and mTOR. Connecting the classic monoaminergic hypothesis with proliferation/neuroplasticity-related evidence is an appealing and comprehensive attempt for improving our knowledge about the neurobiological events leading to depression and associated to antidepressant therapies.
Asunto(s)
Antidepresivos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Trastorno Depresivo/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Antidepresivos/farmacología , Trastorno Depresivo/fisiopatología , Hipocampo/fisiopatología , Humanos , Plasticidad Neuronal/fisiología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
Major depressive disorder is a highly prevalent psychiatric condition. Metalloproteinase 9 (MMP-9), a gelatinase involved in synaptic plasticity, learning and memory processes, is elevated in both chronic stress animal models and human peripheral blood samples of depressed patients. In this study we have evaluated the MMP-9 activity and protein expression in brain areas relevant to depression using the chronic corticosterone mouse model of depression. These mice show a depressive- and anxious-like behaviour. The MMP-9 activity and protein levels are significantly elevated in both the hippocampus and the cortex, and nectin-3 levels are lower in these brain areas in this model. In particular, these mice display an increased gelatinase activity in the CA1 and CA3 subfields of the hippocampus and in the internal layer of the prefrontal cortex. Moreover, the immobility time in the tail suspension test presents a positive correlation with the cortical MMP-9 activity, and a negative correlation with nectin-3 levels. In conclusion, the chronic corticosterone model of depression leads to an increase in the protein expression and activity of MMP-9 and a reduction of its substrate nectin-3 in relevant areas implicated in this disease. The MMP-9 activity correlates with behavioural despair in this model of depression. All these findings support the role of MMP-9 in the pathophysiology of depression, and as a putative target to develop novel antidepressant drugs.
Asunto(s)
Corticosterona , Trastorno Depresivo Mayor , Animales , Humanos , Ratones , Antidepresivos/uso terapéutico , Conducta Animal , Depresión/metabolismo , Trastorno Depresivo Mayor/tratamiento farmacológico , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/uso terapéutico , Nectinas/metabolismoRESUMEN
It has been recently suggested that activation of 5-HT4 receptors might exert antidepressant-like effects in rats after 3 d treatment, suggesting a new strategy for developing faster-acting antidepressants. We studied the effects of 3 d and 7 d treatment with the 5-HT4 receptor partial agonist RS67333 (1.5 mg/kg.d) in behavioural tests of chronic efficacy and on neuroplastic-associated changes, such as adult hippocampal neurogenesis, expression of CREB, BDNF, ß-catenin, AKT and 5-HT4 receptor functionality. RS67333 treatment up-regulated hippocampal cell proliferation, ß-catenin expression and pCREB/CREB ratio after 3 d treatment. This short-term treatment also reduced immobility time in the forced swim test (FST), together with a partial reversion of the anhedonic-like state (sucrose consumption after chronic corticosterone). Administration of RS67333 for 7 d resulted in a higher increase in the rate of hippocampal cell proliferation, a significant desensitization of 5-HT4 receptor-coupled adenylate cyclase activity and a more marked increase in the expression of neuroplasticity-related proteins (BDNF, CREB, AKT): these changes reached the same magnitude as those observed after 3 wk administration of classical antidepressants. Consistently, a positive behavioural response in the novelty suppressed feeding (NSF) test and a complete reversion of the anhedonic-like state (sucrose consumption) were also observed after 7 d treatment. These results support the antidepressant-like profile of RS67333 with a shorter onset of action and suggest that this time period of administration (3-7 d) could be a good approximation to experimentally predict the onset of action of this promising strategy.
Asunto(s)
Compuestos de Anilina/farmacología , Conducta Animal/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Proteínas del Tejido Nervioso/efectos de los fármacos , Vías Nerviosas/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Piperidinas/farmacología , Compuestos de Anilina/administración & dosificación , Animales , Antidepresivos/farmacología , Masculino , Piperidinas/administración & dosificación , Ratas , Ratas Sprague-DawleyRESUMEN
The aim of this study was to use a region-of-interest approach with magnetic resonance imaging to examine the volume of the straight gyrus volume change in first-episode schizophrenia-spectrum patients compared with healthy subjects over a 1-year follow-up period. We did not find a differential pattern of volumetric change between the two groups.
Asunto(s)
Fibras Nerviosas Amielínicas/patología , Corteza Prefrontal/patología , Trastornos Psicóticos/patología , Esquizofrenia/patología , Adulto , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Estudios Longitudinales , Masculino , Tamaño de los ÓrganosRESUMEN
Clinical and preclinical studies report the implication of 5-hydroxytryptamine 4 receptors (5-HT4Rs) in depression and anxiety. Here, we tested whether the absence of 5-HT4Rs influences the response to the antidepressant fluoxetine in mice subjected to chronic corticosterone administration, an animal model of depression and anxiety. Therefore, the effects of chronic administration of fluoxetine in corticosterone-treated wild-type (WT) and 5-HT4R knockout (KO) mice were evaluated in the open-field and novelty suppressed feeding tests. As 5-HT1A receptor (5-HT1AR) and brain-derived neurotrophic factor (BDNF) are critically involved in depression and anxiety, we further evaluated 5-HT1A receptor functionality by [35S]GTPγS autoradiography and BDNF mRNA expression by in situ hybridization techniques. We found that 5-HT4R KO and WT mice displayed anxiety- and depressive-like behavior following chronic administration of corticosterone, as evidenced in the open-field and novelty suppressed feeding tests. In the open-field, a decreased central activity was observed in naiÌve and corticosterone-treated mice of both genotypes following chronic fluoxetine administration. In the novelty suppressed feeding test, a predictive paradigm of antidepressant activity, chronic treatment with fluoxetine reverted the latency to eat in both genotypes. The antidepressant also potentiated the corticosterone-induced desensitization of the 5-HT1AR in the dorsal raphe nucleus. Further, chronic fluoxetine increased BDNF mRNA expression in the dentate gyrus of the hippocampus in corticosterone-treated mice of both genotypes. Therefore, our findings indicate that the behavioral effects of fluoxetine in the corticosterone model of depression and anxiety appear not to be dependent on 5-HT4Rs.
Asunto(s)
Corticosterona , Fluoxetina , Animales , Ansiedad , Depresión/tratamiento farmacológico , Fluoxetina/farmacología , Hipocampo , Ratones , SerotoninaRESUMEN
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 30â¯mg/kg was administered systemically to mice 30â¯min before lipopolysaccharide (LPS; 0.83â¯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.
Asunto(s)
Antidepresivos/uso terapéutico , Cannabidiol/uso terapéutico , Depresión/tratamiento farmacológico , Depresión/metabolismo , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/toxicidad , Animales , Antidepresivos/farmacología , Cannabidiol/farmacología , Depresión/inducido químicamente , Suspensión Trasera/efectos adversos , Suspensión Trasera/psicología , Mediadores de Inflamación/antagonistas & inhibidores , Masculino , RatonesRESUMEN
Increasing data indicate that brain endocannabinoid system plays a role in the effects of antidepressant medications. Here we examined the effect of in vivo exposure to the selective serotonin uptake inhibitor fluoxetine on cannabinoid type 1 (CB(1)) receptor density and functionality in the rat prefrontal cortex (PFC) and cerebellum. Long-term treatment with fluoxetine (10 mg/kg/day) enhanced CB(1) receptor inhibition of adenylyl cyclase (AC) in the PFC and reduced it in the cerebellum without altering receptor density and agonist stimulation of guanosine 5'-O-(3-[(35)S]thio) triphosphate ([(35)S]GTP gamma S) in either area. Analysis of [(35)S]GTP gamma S-labeled G alpha subunits allowed for the detection of up-regulated CB(1) receptor coupling to G alpha(i2), G alpha(i3) in the PFC, and reduced coupling to G alpha(i3) in the cerebellum of fluoxetine-treated rats. Concomitant administration of the 5-HT(1A) receptor antagonist N-[2-[4- (2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate (WAY100635; 0.1 mg/kg/day) reduced fluoxetine-induced modulation of CB(1) receptor coupling to G alpha subunits and AC in the PFC but not in the cerebellum. These results indicate that increased CB(1) receptor signaling at the G alpha(i)-AC transduction level is a long-term adaptation induced by fluoxetine in the PFC and point to a role for 5-HT(1A) receptors in this effect. Basal AC activity, protein kinase A (PKA) catalytic subunit expression, and phospho-cAMP response element-binding protein (pCREB)/CREB ratio were also up-regulated in the PFC of fluoxetine-treated animals, whereas no differences were detected in the cerebellum. It is interesting that long-term Delta(9)-tetrahydrocannabinol treatment did not elicit antidepressant-like effects or modulated behavioral responses of fluoxetine in an animal model of depression (olfactory bulbectomy). These data suggest that altered signal transduction through CB(1) receptors in the PFC may participate in the regulation of the AC-PKA-CREB cascade induced by fluoxetine in this brain area.
Asunto(s)
Inhibidores de Adenilato Ciclasa , Fluoxetina/administración & dosificación , Corteza Prefrontal/fisiología , Receptor Cannabinoide CB1/fisiología , Receptor de Serotonina 5-HT1A/fisiología , Adenilil Ciclasas/metabolismo , Animales , Benzoxazinas/administración & dosificación , Cannabinoides/administración & dosificación , Relación Dosis-Respuesta a Droga , Masculino , Morfolinas/administración & dosificación , Naftalenos/administración & dosificación , Corteza Prefrontal/efectos de los fármacos , Distribución Aleatoria , Ratas , Ratas Wistar , Receptor Cannabinoide CB1/agonistas , Factores de TiempoRESUMEN
5-HT1A receptors couple to different Go/Gi proteins in order to mediate a wide range of physiological actions. While activation of post-synaptic 5-HT1A receptors is mainly related to inhibition of adenylyl cyclase activity, functionality of autoreceptors located in raphe nuclei has been classically ascribed to modifications of the activity of potassium and calcium channels. In order to evaluate the possible existence of agonist-directed trafficking for 5-HT1A autoreceptors in the rat dorsal raphe nucleus, we studied their activation by two agonists with a different profile of efficacy [(+)8-OH-DPAT and buspirone], addressing simultaneously the identification of the specific Galpha subtypes ([35S]GTPgammaS labelling and immunoprecipitation) involved and the subsequent changes in cAMP formation. A significant increase (32%, p<0.05) in (+)8-OH-DPAT-induced [35S]GTPgammaS labelling of immunoprecipitates was obtained with anti-Galphai3 antibodies but not with anti-Galphao, anti-Galphai1, anti-Galphai2, anti-Galphaz or anti-Galphas antibodies. In contrast, in the presence of buspirone, significant [35S]GTPgammaS labelling of immunoprecipitates was obtained with anti-Galphai3 (50%, p<0.01), anti-Galphao (32%, p<0.01) and anti-Galphai2 (29%, p<0.05) antibodies, without any labelling with anti-Galphai1, anti-Galphaz or anti-Galphas. The selective 5-HT1A antagonist WAY 100635 blocked the labelling induced by both agonists. Furthermore, (+)8-OH-DPAT failed to modify forskolin-stimulated cAMP accumulation, while buspirone induced a dose-dependent, WAY 100635-sensitive, inhibition of this response (Imax 30.8+/-4.9, pIC50 5.95+/-0.46). These results demonstrate the existence of an agonist-dependency pattern of G-protein coupling and transduction for 5-HT1A autoreceptors in native brain tissue. These data also open new perspectives for the understanding of the differential profiles of agonist efficacy in pre- vs. post-synaptic 5-HT1A receptor-associated responses.
Asunto(s)
Proteínas de Unión al GTP/metabolismo , Núcleos del Rafe/efectos de los fármacos , Receptor de Serotonina 5-HT1A/metabolismo , Agonistas del Receptor de Serotonina 5-HT1/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Inhibidores de Adenilato Ciclasa , Adenilil Ciclasas/metabolismo , Animales , Buspirona/farmacología , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Masculino , Núcleos del Rafe/metabolismo , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacosRESUMEN
Studies of the temporal pole (TP) in schizophrenia patients are not consistent. The aim of this study was to investigate morphometric anomalies of the TP in first-episode schizophrenia patients. Patients did not significantly differ from controls in the TP morphometric variables evaluated. Clinical variables were not significantly related to the TP.
Asunto(s)
Mapeo Encefálico , Esquizofrenia/patología , Lóbulo Temporal/patología , Adulto , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Masculino , Escalas de Valoración Psiquiátrica , Esquizofrenia/fisiopatología , Estadística como Asunto , Adulto JovenRESUMEN
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.
Asunto(s)
Ansiedad/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Serotonina/metabolismo , beta Catenina/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Corticosterona/metabolismo , Depresión/metabolismo , Hipocampo/metabolismo , Masculino , Ratones , Corteza Prefrontal/metabolismoRESUMEN
Bilateral olfactory bulbectomy in the rat (OBX) induces behavioral, neurochemical, and structural abnormalities similar to those observed in human depression that are normalized after chronic, but not acute, treatment with antidepressants. In our study, OBX animals exhibited significant increases in both CB(1) receptor density ([(3)H]CP55490 binding) and functionality (stimulation of [(35)S]GTPgammaS binding by the cannabinoid (CB) agonist WIN 55212-2) at the prefrontal cortex (PFC). After chronic treatment with fluoxetine (10 mg/kg/day, 14 days, s.c.), OBX-induced hyperactivity in the open-field test was fully abolished. Interestingly, chronic fluoxetine fully reversed the enhanced CB(1)-receptor signaling in PFC observed following OBX. The CB agonist Delta(9)-tetrahydrocannabinol (5 mg/kg, i.p., 1 day) did not produce any behavioral effect in sham-operated animals but returned locomotor activity to control values in OBX rats. As both acute administration of Delta(9)-tetrahydrocannabinol and chronic fluoxetine elicited a similar behavioral effect in the OBX rat, it is not unlikely that the regionally selective enhancement of CB(1) receptor-signaling in the PFC could be related with the altered OBX behavior. Our findings reinforce the utility of this animal model to further investigating the implication of the endocannabinoid system in the modulation of emotional processes and its potential role in the adaptive responses to chronic antidepressants.
Asunto(s)
Antidepresivos de Segunda Generación/administración & dosificación , Depresión/patología , Fluoxetina/administración & dosificación , Corteza Prefrontal/efectos de los fármacos , Receptor Cannabinoide CB1/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Autorradiografía , Ciclohexanoles/metabolismo , Depresión/tratamiento farmacológico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Dronabinol/análogos & derivados , Dronabinol/farmacología , Esquema de Medicación , Conducta Exploratoria/efectos de los fármacos , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Inmunosupresores/metabolismo , Isótopos/metabolismo , Masculino , Bulbo Olfatorio/lesiones , Corteza Prefrontal/metabolismo , Unión Proteica/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
The mode of action of antidepressant drugs may be related to mechanisms of monoamines receptor adaptation, including serotonin 5-HT(4) receptor subtypes. Here we investigated the effects of repeated treatment with the selective serotonin reuptake inhibitor fluoxetine for 21 days (5 and 10 mg/kg, p.o., once daily) on the sensitivity of 5-HT(4) receptors by using receptor autoradiography, adenylate cyclase assays and extracellular recording techniques in rat brain. Fluoxetine treatment decreased the density of 5-HT(4) receptor binding in the CA1 field of hippocampus as well as in several areas of the striatum over the doses of 5-10 mg/kg. In a similar way, we found a significant lower response to zacopride-stimulated adenylate cyclase activity in the fluoxetine 10 mg/kg/day treated group. Furthermore, post-synaptic 5-HT(4) receptor activity in hippocampus-measured as the excitatory action of zacopride in the pyramidal cells of CA1 evoked by Schaffer collateral stimulation was attenuated in rats treated with both doses of fluoxetine. Taken together, these results support the concept that a net decrease in the signalization pathway of 5-HT(4) receptors occurs after chronic selective serotonin reuptake inhibitor treatment: this effect may underlie the therapeutic efficacy of these drugs.
Asunto(s)
Encéfalo/fisiología , Fluoxetina/administración & dosificación , Receptores de Serotonina 5-HT4/fisiología , Transducción de Señal/fisiología , Adenilil Ciclasas/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Factores de TiempoRESUMEN
S 47445 is a positive allosteric modulator of glutamate AMPA-type receptors that possesses procognitive, neurotrophic and enhancing synaptic plasticity properties. Its chronic administration promotes antidepressant- and anxiolytic-like effects in different rodent models of depression. We have evaluated the behavioral effects of S 47445 in the bilateral olfactory bulbectomy mice model (OB) and the adaptive changes in those proteins associated to brain neuroplasticity (BDNF and mTOR pathway). Following OB surgery, adult C57BL/6J male mice were chronically administered S 47445 (1, 3 and 10â¯mg/kg/day; i.p.) and fluoxetine (18â¯mg/kg/day; i.p.), and then behaviorally tested in the open field test. Afterwards, the expression levels of BDNF, mTOR, phospho-mTOR, 4EBP1 and phospho-4EBP1 were evaluated in hippocampus and prefrontal cortex. Both drugs reduced the OB-induced locomotor activity, a predictive outcome of antidepressant efficacy, with a similar temporal pattern of action. S 47445, but not fluoxetine, showed an anxiolytic effect as reflected by an increased central activity. Chronic administration of S 47445 reversed OB-induced changes in BDNF and phopho-mTOR expression in hippocampus but not in prefrontal cortex. The chronic administration of S 47445 induced antidepressant- and anxiolytic-like effects at low-medium doses (1 and 3â¯mg/kg/day, i.p.) associated with the reversal of OB-induced changes in hippocampal BDNF and mTOR signaling pathways.
Asunto(s)
Ansiolíticos/farmacología , Antidepresivos/farmacología , Benzoxazinas/farmacología , Hipocampo/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Bulbo Olfatorio/cirugía , Triazinas/farmacología , Animales , Antidepresivos de Segunda Generación/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Fluoxetina/farmacología , Hipocampo/metabolismo , Hipocampo/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Bulbo Olfatorio/fisiología , Receptores AMPA/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
ß-catenin (key mediator in the Wnt signaling pathway) contributes to the pathophysiology of mood disorders, associated to neurogenesis and neuroplasticity. Decreased ß-catenin protein levels have been observed in the hippocampus and prefrontal cortex of depressed subjects. Additionally, the antidepressants exert, at least in part, their neurogenic effects by increasing ß-catenin levels in the subgranular zone of the hippocampus. To further understand the role of ß-catenin in depression and anxiety, we generated two conditional transgenic mice in which ß-catenin was either inactivated or stabilized in cells expressing CreERT under the control of the astrocyte-specific glutamate transporter (GLAST) promoter inducible by tamoxifen, which presents high expression levels on the subgranular zone of the hippocampus. Here, we show that ß-catenin inactivation in GLAST-expressing cells enhanced anxious/depressive-like responses. These behavioral changes were associated with impaired hippocampal proliferation and markers of immature neurons as doublecortin. On the other hand, ß-catenin stabilization induced an anxiolytic-like effect in the novelty suppressed feeding test and tended to ameliorate depressive-related behaviors. In these mice, the control over the Wnt/ß-catenin pathway seems to be tighter as evidenced by the lack of changes in some proliferation markers. Moreover, animals with stabilized ß-catenin showed resilience to some anxious/depressive manifestations when subjected to the corticosterone model of depression. Our findings demonstrate that ß-catenin present in GLAST-expressing cells plays a critical role in the development of anxious/depressive-like behaviors and resilience, which parallels its regulatory function on hippocampal proliferation. Further studies need to be done to clarify the importance of these changes in other brain areas also implicated in the neurobiology of anxiety and depressive disorders.