RESUMEN
Psychosocial stress has increased considerably in our modern lifestyle, affecting global mental health. Deficits in attentional control are cardinal features of stress disorders and pathological anxiety. Studies suggest that changes in the locus coeruleus-norepinephrine system could underlie the effects of stress on top-down attentional control. However, the impact of psychosocial stress on attentional processes and its underlying neural mechanisms are poorly understood. This study aims to investigate the effect of psychosocial stress on attentional processing and brain signatures. Evoked potentials and pupillary activity related to the oddball auditory paradigm were recorded before and after applying the Montreal Imaging Stress Task (MIST). Electrocardiogram (ECG), salivary cortisol, and subjective anxiety/stress levels were measured at different experimental periods. The control group experienced the same physical and cognitive effort but without the psychosocial stress component. The results showed that stressed subjects exhibited decreased P3a and P3b amplitude, pupil phasic response, and correct responses. On the other hand, they displayed an increase in Mismatch Negativity (MMN). N1 amplitude after MIST only decreased in the control group. We found that differences in P3b amplitude between the first and second oddball were significantly correlated with pupillary dilation and salivary cortisol levels. Our results suggest that under social-evaluative threat, basal activity of the coeruleus-norepinephrine system increases, enhancing alertness and decreasing voluntary attentional resources for the cognitive task. These findings contribute to understanding the neurobiological basis of attentional changes in pathologies associated with chronic psychosocial stress.
RESUMEN
The foetal brain is highly susceptible to stress in late pregnancy, with lifelong effects of stress on physiology and behaviour. The present study aimed to determine the physiological and behavioural effects of prenatal stress during the prepubertal period of female and male rats. We subjected pregnant Sprague-Dawley rats to a restraint stress protocol from gestational day 14 to 21, a critical period for foetal brain susceptibility to stress effects. Male and female offspring were subsequently assessed at postnatal day 24 for anxiety- and depressive-like behaviours, as well as spontaneous social interaction. We also assessed maternal behaviours and 2 stress markers: basal vs acute-evoked stress levels of serum corticosterone and body weight gain. Prenatal stress did not affect the maternal behaviour, whereas both female and male offspring had higher body weight gain. On the other hand, lower levels of corticosterone after acute stress stimulation, as well as anxiety- and depressive-like behaviours, were only evident in stressed males compared to control males. These results suggest that prenatal stress induced sex-specific effects on hypothalamic-pituitary-adrenal (HPA) axis activity and on behaviour during prepuberty. The HPA axis of prenatally stressed male rats was less active compared to control males, and they were also more anxious and experienced depressive-like behaviours. These results are useful with respect to studying the neurobiological basis of childhood depression at a preclinical level.
Asunto(s)
Ansiedad/metabolismo , Peso Corporal/fisiología , Corticosterona/sangre , Depresión/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Estrés Fisiológico/fisiología , Estrés Psicológico/metabolismo , Animales , Conducta Animal/fisiología , Femenino , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Sistema Hipófiso-Suprarrenal/metabolismo , Embarazo , Ratas , Ratas Sprague-Dawley , Restricción Física , Factores SexualesRESUMEN
Research in programming has focused in the study of stimuli that affect sensitive periods of development such as prenatal and neonatal stage. We previously showed that exposure to estradiol valerate to female rats during the first 12 h of life increased catecholamine content in ventromedial-arcuatus hypothalamus of the adult rat. However, changes in others dopaminergic circuits have not been studied. The purpose of this work was to determine the neurotransmitters changes induced by neonatal estradiol valerate (0.1 mg/50 µl s. c. per rat) administration on nigrostriatal pathway of adult female rats. Sesame oil (50 µl s. c. per rat) was administered in a control parallel group. EV-1 adult rats presented effective markers of long-term estrogenization as decreased serum levels of progesterone and a reduction in the size of estrogen-sensitive organs. In the brain, neonatal estradiol valerate administration led to a significant increase in dopamine content in striatum, substantia nigra and ventral tegmental area. With respect to the contents of dopamine metabolites, only 3-methoxytyramine content increased in substantia nigra and ventral tegmental area. In addition, the content of noradrenaline increased only in striatum. Interestingly, estrogenized rats lacked locomotor activity induced by acute dose of amphetamine (1 mg/kg i. p.). Altogether, these results show that neonatal exposure to estradiol valerate permanently modified the content of monoamine neurotransmitters in nigrostriatal pathway and amphetamine-induced locomotor activity of adult female rats. This might imply that estrogenized rats could have changes in the expression of key proteins in dopaminergic regulation, as tyrosine hydroxylase and dopamine transporter.
Asunto(s)
Dopamina/metabolismo , Estradiol/análogos & derivados , Sustancia Negra/metabolismo , Anfetamina/metabolismo , Animales , Animales Recién Nacidos , Cuerpo Estriado/crecimiento & desarrollo , Cuerpo Estriado/metabolismo , Estradiol/metabolismo , Femenino , Actividad Motora , Neurotransmisores/metabolismo , Ratas , Ratas Sprague-Dawley , Sustancia Negra/crecimiento & desarrolloRESUMEN
It has been postulated that chronic administration of antidepressant drugs induces delayed structural and molecular adaptations at glutamatergic forebrain synapses that might underlie mood improvement. To gain further insight into these changes in the cerebral cortex, rats were treated with fluoxetine (flx) for 4 weeks. These animals showed decreased anxiety and learned helplessness. N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunit levels (NR1, NR2A, NR2B, GluR1 and GluR2) were analysed in the forebrain by both western blot of homogenates and immunohistochemistry. Both methods demonstrated an upregulation of NR2A, GluR1 and GluR2 that was especially significant in the retrosplenial granular b cortex (RSGb). However, when analysing subunit content in postsynaptic densities and synaptic membranes, we found increases of NR2A and GluR2 but not GluR1. Instead, GluR1 was augmented in a microsomal fraction containing intracellular membranes. NR1 and GluR2 were co-immunoprecipitated from postsynaptic densities and synaptic membranes. In the immunoprecipitates, NR2A was increased while GluR1 was decreased supporting a change in receptor stoichiometry. The changes of subunit levels were associated with an upregulation of dendritic spine density and of large, mushroom-type spines. These molecular and structural adaptations might be involved in neuronal network stabilization following long-term flx treatment.
Asunto(s)
Antidepresivos/farmacología , Fluoxetina/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Ácido Glutámico/fisiología , Plasticidad Neuronal/efectos de los fármacos , Prosencéfalo/efectos de los fármacos , Receptores AMPA/biosíntesis , Receptores de N-Metil-D-Aspartato/biosíntesis , Animales , Ansiedad/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/metabolismo , Desamparo Adquirido , Membranas Intracelulares/efectos de los fármacos , Membranas Intracelulares/metabolismo , Masculino , Microsomas/efectos de los fármacos , Microsomas/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/ultraestructura , Densidad Postsináptica/efectos de los fármacos , Densidad Postsináptica/metabolismo , Prosencéfalo/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores AMPA/genética , Receptores de N-Metil-D-Aspartato/genética , Membranas Sinápticas/efectos de los fármacos , Membranas Sinápticas/metabolismoRESUMEN
Chronic stress affects brain areas involved in learning and emotional responses. These alterations have been related with the development of cognitive deficits in major depression. The aim of this study was to determine the effect of chronic immobilization stress on the auditory and visual mesencephalic regions in the rat brain. We analyzed in Golgi preparations whether stress impairs the neuronal morphology of the inferior (auditory processing) and superior colliculi (visual processing). Afterward, we examined the effect of stress on acoustic and visual conditioning using an avoidance conditioning test. We found that stress induced dendritic atrophy in inferior colliculus neurons and did not affect neuronal morphology in the superior colliculus. Furthermore, stressed rats showed a stronger impairment in acoustic conditioning than in visual conditioning. Fifteen days post-stress the inferior colliculus neurons completely restored their dendritic structure, showing a high level of neural plasticity that is correlated with an improvement in acoustic learning. These results suggest that chronic stress has more deleterious effects in the subcortical auditory system than in the visual system and may affect the aversive system and fear-like behaviors. Our study opens a new approach to understand the pathophysiology of stress and stress-related disorders such as major depression.
Asunto(s)
Conducta Animal/fisiología , Condicionamiento Clásico/fisiología , Neuronas/patología , Estrés Psicológico/patología , Estrés Psicológico/fisiopatología , Estimulación Acústica , Animales , Reacción de Prevención/fisiología , Masculino , Aprendizaje por Laberinto/fisiología , Estimulación Luminosa , Ratas , Ratas Sprague-DawleyRESUMEN
Monoamine oxidase-A (MAO-A) [amiflamine (AMF) and 4-methylthioamphetamine (MTA)] and MAO-B (L-deprenyl) inhibitors were found to be cytotoxic in a concentration-dependent manner for RCHT cells derived from adult rat hypothalamus. The cytotoxic effects were increased when the inhibitors were co-incubated with dicoumarol and especially with 25 micro M AMF+100 micro M dicoumarol (2.5-fold; P <0.001). The treatment of RCHT cells solely with AMF induced a marked decrease in the expression of DT-diaphorase mRNA.
RESUMEN
The endogenous dopamine-derived neurotoxin salsolinol was found to decrease survival in the dopaminergic neuronal cell line RCSN-3, derived from adult rat substantia nigra in a concentration-dependent manner (208 microM salsolinol induced a 50% survival decrease). Incubation of RCSN-3 cells with 100 micro;M dicoumarol and salsolinol significantly decreased cell survival by 2.5-fold (P < 0.001), contrasting with a negligible effect on RCHT cells, which exhibited nearly a 5-fold lower nomifensine-insensitive dopamine uptake. The levels of catalase and glutathione peroxidase mRNA were decreased when RCSN-3 cells were treated with 100 microM salsolinol alone or in the presence of 100 microM dicoumarol. In vitro oxidation of salsolinol to o-quinone catalyzed by lactoperoxidase gave the quinone methide and 1,2-dihydro-1-methyl-6,7-isoquinoline diol as final products of salsolinol oxidation as determined by NMR analysis. Evidence of the formation of salsolinol o-semiquinone radical has been provided by ESR studies during one-electron oxidation of salsolinol catalyzed by lactoperoxidase.
Asunto(s)
Supervivencia Celular/efectos de los fármacos , Dopamina/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Indolquinonas , Indoles/farmacología , Isoquinolinas/farmacología , Neuronas/efectos de los fármacos , Quinonas/farmacología , Animales , Transporte Biológico/efectos de los fármacos , Catalasa/genética , Línea Celular , Dicumarol/farmacología , Espectroscopía de Resonancia por Spin del Electrón , Glutatión Peroxidasa/genética , Neuronas/citología , Neuronas/metabolismo , ARN Mensajero/genética , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sustancia Negra/citología , Superóxido Dismutasa/genética , Transcripción Genética/efectos de los fármacosRESUMEN
The mechanism of copper (Cu) neurotoxicity was studied in the RCSN-3 neuronal dopaminergic cell line, derived from substantia nigra of an adult rat. The formation of a Cu-dopamine complex was accompanied by oxidation of dopamine to aminochrome. We found that the Cu-dopamine complex mediates the uptake of (64)CuSO(4) into the Raúl Caviedes substantia nigra-clone 3 (RCSN3) cells, and it is inhibited by the addition of excess dopamine (2 m M) (63%, p < 0.001) and nomifensine (2 microM) (77%, p < 0.001). Copper sulfate (1 m M) alone was not toxic to RCSN-3 cells, but was when combined with dopamine or with dicoumarol (95% toxicity; p < 0.001) which inhibits DPNH and TPNH (DT)-diaphorase. Electron spin resonance (ESR) spectrum of the 5,5-dimethylpyrroline-N-oxide (DMPO) spin trap adducts showed the presence of a C-centered radical when incubating cells with dopamine, CuSO(4) and dicoumarol. A decrease in the expression of CuZn-superoxide dismutase and glutathione peroxidase mRNA was observed when RCSN-3 cells were treated with CuSO(4), dopamine, or CuSO(4) and dopamine. However, the mRNA expression of glutathione peroxidase remained at control levels when the cells were treated with CuSO(4), dopamine and dicoumarol. The regulation of catalase was different since all the treatments with CuSO(4) increased the expression of catalase mRNA. Our results suggest that copper neurotoxicity is dependent on: (i) the formation of Cu-dopamine complexes with concomitant dopamine oxidation to aminochrome; (ii) dopamine-dependent Cu uptake; and (iii) one-electron reduction of aminochrome.
Asunto(s)
Sulfato de Cobre/toxicidad , Dopamina/farmacología , Indolquinonas , Indoles/metabolismo , Transporte Iónico/efectos de los fármacos , Neuronas/efectos de los fármacos , Sustancia Negra/citología , Animales , Catalasa/biosíntesis , Catalasa/genética , Línea Celular , Sulfato de Cobre/metabolismo , Sulfato de Cobre/farmacología , Dicumarol/toxicidad , Espectroscopía de Resonancia por Spin del Electrón , Inducción Enzimática/efectos de los fármacos , Glutatión Peroxidasa/biosíntesis , Glutatión Peroxidasa/genética , Metalotioneína/metabolismo , NAD(P)H Deshidrogenasa (Quinona)/biosíntesis , NAD(P)H Deshidrogenasa (Quinona)/genética , Neuronas/metabolismo , Nomifensina/farmacología , Oxidación-Reducción , Estrés Oxidativo , Enfermedad de Parkinson/metabolismo , ARN Mensajero/biosíntesis , Ratas , Superóxido Dismutasa/biosíntesis , Superóxido Dismutasa/genéticaRESUMEN
Human glutathione transferase M2-2 prevents the formation of neurotoxic aminochrome and dopachrome by catalyzing the conjugation of dopamine and dopa o-quinone with glutathione. NMR analysis of dopamine and dopa o-quinone-glutathione conjugates revealed that the addition of glutathione was at C-5 to form 5-S-glutathionyl-dopamine and 5-S-glutathionyl-dopa, respectively. Both conjugates were found to be resistant to oxidation by biological oxidizing agents such as O(2), H(2)O(2), and O(*-)(2), and the glutathione transferase-catalyzed reaction can therefore serve a neuroprotective antioxidant function.