Citalopram reduces glutamatergic synaptic transmission in the auditory cortex via activation of 5-HT1A receptors.

Serotonin modulates cognitive processes and is related to various psychiatric disorders, including major depression. Administration of citalopram reduces the amplitude of auditory evoked potentials in depressed people and animal models, suggesting that 5-HT has an inhibitory role. Here, we characterize the modulation of excitatory post-synaptic currents by application of either 5-HT or agonists of 5-HT1A and 5-HT2 receptors, or by endogenous 5-HT evoked by citalopram on pyramidal neurons from layer II/III of rat auditory cortex. We found that application of 5-HT concentration-dependently reduces excitatory post-synaptic currents amplitude without changing the paired-pulse ratio, suggesting a post-synaptic modulation. We observed that selective agonists of 5-HT1A and 5-HT2 receptors [8-OH-DPAT (10 µM) and DOI (10 µM), respectively] mimic the effect of 5-HT on the excitatory post-synaptic currents. Effect of 5-HT was entirely blocked by co-application of the antagonists NAN-190 (1 µM) and ritanserin (200 nM). Similarly, citalopram application (1 µM) reduced the amplitude of the evoked excitatory post-synaptic currents. Reduction in the magnitude of the excitatory post-synaptic currents by endogenous 5-HT was interpolated in the dose-response curve elicited by exogenous 5-HT, yielding that citalopram raised the extracellular 5-HT concentration to 823 nM. Effect of citalopram was blocked by the previous application of NAN-190 but not ritanserin, indicating that citalopram reduces glutamatergic synaptic transmission via 5-HT1A receptors in layer II/III of the auditory cortex. These results suggest that the local activity of 5-HT contributes to decrease in the basal excitability of the auditory cortex for enhancing the detection of external relevant acoustic signals.

Relación entre la sobrecarga y el índice depresivo de cuidadores primarios de pacientes con enfermedades neuromusculoesqueléticas / The relationship between the overload and the depressive index of primary caregivers of patients with neuromusculoskeletal diseases

Resumen Introducción Una enfermedad neuromusculoesquelética no solo afecta a la persona que la padece, sino que también repercute de manera directa en la familia y en particular al cuidador primario informal. Las labores de cuidado incrementan la morbilidad psicológica y el estrés de los cuidadores primarios. El objetivo del presente estudio consiste en identificar la relación entre la sobrecarga y el índice de depresión presente en los cuidadores primarios informales de pacientes con enfermedad neuromusculoesquelética. Material y Métodos Se realizó un estudio exploratorio que incluyó a 18 cuidadores primarios informales de pacientes con enfermedad neuromusculoesquelética, y que asistieron a consulta en la Unidad Universitaria de Rehabilitación de la Universidad Autónoma de Yucatán. Resultados Entre las características sociodemográficas predominaron las cuidadoras del sexo femenino (83%) con parentesco familiar con el paciente. Además, predomino entre los cuidadores primarios el estado civil casado y un nivel de estudios de licenciatura. La relación entre la sobrecarga y el índice de depresión fue elevada y significativa (r=0.72, p=0.0007). En conclusión, estos resultados sugieren que, a mayor sobrecarga producida por las labores del cuidado, mayor será el grado de afectación en el estado anímico del cuidador primario informal. Este estudio ayudará en la elaboración de un programa de intervención para prevenir la sobrecarga en cuidadoras primarias informales.

Abstract Introduction A neuromusculoskeletal disease not only affects the person who suffers it but also directly affects the family and in particular with the informal primary caregiver. Care work increases the psychological morbidity and stress of primary caregivers. The aim of the present study was to identify the relationship between overload and the rate of depression present in informal primary caregivers of patients with the neuromusculoskeletal disease. Methods An exploratory study was carried out that included 18 informal primary caregivers of patients with the neuromusculoskeletal disease, and who attended a consultation at the University Rehabilitation Unit of the Autonomous University of Yucatan. Results Among the sociodemographic characteristics, female caregivers prevailed (83%) with a family relationship with the patient. Also, primary married status and a bachelor's degree level predominated among primary caregivers. The relationship between overload and depression index was high and significant (r = 0.72, p = 0.0007). In conclusion, these results suggest that the greater the overload produced by the tasks of care, the greater the degree of involvement in the state of the informal primary caregiver. This study will help in the development of an intervention program to prevent overload in informal primary caregivers.

A new theory of depression based on the serotonin/kynurenine relationship and the hypothalamicpituitary- adrenal axis

The serotonergic and immunological hypothesis of depression proposes that certain types of excessive stress distort the relationship between the activities of the innate immune and central nervous systems, so that the stress caused by an infection, or excessive psychological stress, activate toll-like receptors such as the TLR-4, the transcription factor NF-kB, the inflammasome NLRP3, as well as the secretion of interleukin-1 beta (IL-1ß), interleukin-6 (IL-6) and other factors of the innate immune response, causing first, the general symptoms of the disease which appear with any infection, but also those characteristic of depressive illness such as dysphoria and anhedonia. The evidence indicates that, if the stimulus persists or recurs within 24 hours, the indole-2, 3-dioxygenase enzyme (IDO) of the kynurenine metabolic pathway, which increases the synthesis of quinolinic acid, is activated with an associated reduction of serotonin synthesis. Quinolinic acid activates NMDA receptors in the central nervous system and stimulates the secretion of interleukins IL-6 and 1L-1ß, among others, promoting hyper-activity of the HPA axis and reinforcing a bias of the tryptophan metabolism to produce quinolinic acid, and interleukins by the innate immune system, further reducing the synthesis of serotonin and consolidating the depressive process. We discuss the evidence showing that this process can be initiated by either interleukin stimulated by an infection or some vaccines or excessive psychological stress that activates the HPA axis together with said innate immune response, causing a process of aseptic inflammation in the central nervous system.

Nueva teoría sobre la depresión: un equilibrio del ánimo entre el sistema nervioso y el inmunológico, con regulación de la serotonina-quinurenina y el eje hipotálamo-hipófiso-suprarrenal / A new theory of depression based on the serotonin/kynurenine relationship and the hypothalamic-pituitary-adrenal axis

La hipótesis sobre las causas de la depresión basada en la acción de la serotonina y del sistema inmunológico, propone que ciertos tipos de estrés distorsionan la relación entre la actividad del sistema inmunitario innato y la del sistema nervioso central. El estrés causado por una infección o el estrés psicológico excesivo activan receptores de tipo toll, como el TLR-4, el factor de transcripción NF-kB, el inflamasoma NLRP3, así como la secreción de interleucina 1 beta (IL-1ß) e interleucina 6 (IL-6); esto causa, en primer lugar, los síntomas generales de enfermedad que aparecen con cualquier infección, pero también los síntomas característicos de la depresión como disforia y anhedonia. Las evidencias indican que, si el estímulo persiste o se repite en las siguientes 24 horas, se activa la enzima indolamina 2,3-dioxigenasa (IDO) de la vía metabólica de la quinurenina, lo cual incrementa la síntesis del ácido quinolínico y reduce la síntesis de serotonina. El ácido quinolínico activa los receptores de N-metil-D-aspartato (NMDA) en el sistema nervioso central y estimula la secreción de, entre otras, las interleucinas IL-6 e 1L-1ß, las cuales promueven la hiperactividad del eje hipotálamohipófiso-suprarrenal y refuerzan la desviación del metabolismo del triptófano hacia la producción de ácido quinolínico, así como de las interleucinas de la inmunidad innata, con lo cual se reduce más la síntesis de serotonina y se consolida el proceso depresivo. Este proceso puede ser iniciado por las interleucinas estimuladas por una infección, así como por algunas vacunas o por un estrés psicológico excesivo que active el eje hipotálamo-hipófiso-suprarrenal simultáneamente con la respuesta inmunológica innata, con lo que se provocaría un proceso de inflamación estéril en el sistema nervioso central.

The serotonergic and immunological hypothesis of depression proposes that certain types of excessive stress distort the relationship between the activities of the innate immune and central nervous systems, so that the stress caused by an infection, or excessive psychological stress, activate toll-like receptors such as the TLR-4, the transcription factor NF-kB, the inflammasome NLRP3, as well as the secretion of interleukin-1 beta (IL-1ß), interleukin-6 (IL-6) and other factors of the innate immune response, causing first, the general symptoms of the disease which appear with any infection, but also those characteristic of depressive illness such as dysphoria and anhedonia. The evidence indicates that, if the stimulus persists or recurs within 24 hours, the indole-2, 3-dioxygenase enzyme (IDO) of the kynurenine metabolic pathway, which increases the synthesis of quinolinic acid, is activated with an associated reduction of serotonin synthesis. Quinolinic acid activates NMDA receptors in the central nervous system and stimulates the secretion of interleukins IL-6 and 1L-1ß, among others, promoting hyper-activity of the HPA axis and reinforcing a bias of the tryptophan metabolism to produce quinolinic acid, and interleukins by the innate immune system, further reducing the synthesis of serotonin and consolidating the depressive process. We discuss the evidence showing that this process can be initiated by either interleukin stimulated by an infection or some vaccines or excessive psychological stress that activates the HPA axis together with said innate immune response, causing a process of aseptic inflammation in the central nervous system.

Prevalencia, causas y tratamiento de la depresión Mayor / Prevalence, Causes, and Treatment of Major Depression

Resumen La depresión mayor representa un problema de salud pública debido a su alta prevalencia. La etiología de la depresión es compleja ya que en ella intervienen factores psicosociales, genéticos, y biológicos. Entre los factores psicosociales, se ha observado que los primeros episodios depresivos aparecen después de algún evento estresante, y el estrés que acompaña al primer episodio produce cambios a largo plazo en la fisiología cerebral que pueden producir variaciones a nivel estructural y en el funcionamiento de diferentes áreas cerebrales. Entre los factores genéticos que intervienen en el trastorno depresivo, se ha reportado que alrededor de 200 genes están relacionados con el trastorno depresivo mayor. Dentro de los factores biológicos, existen evidencias de alteraciones a nivel de neurotransmisores, citosinas y hormonas, cuyas acciones inducen modificaciones estructurales y funcionales en el sistema nervioso central, en el sistema inmunológico y en el sistema endocrino, que incrementan el riesgo de padecer la depresión mayor. A pesar de años de estudio, las bases biológicas del trastorno depresivo mayor y el mecanismo preciso de la eficacia antidepresiva siguen siendo poco claras. El objetivo de la presente revisión es resumir las principales conclusiones de la literatura clínica y experimental en relación con la etiología del trastorno depresivo mayor.

Abstract Major depression represents a public health problem due to its high prevalence. The etiology of major depression is complex because involves psychosocial, genetic, and biological factors. Among psychosocial factors, different studies report that the first depressive episode appear after some stressful event and produces long-term changes in brain physiology. These long-lasting changes produce variations at the structural level and in the functioning of different brain areas. Among the genetic factors involved in depressive illness, it has been reported that about 200 genes are related to major depressive disorder. Within the biological factors, there is an evidence of alterations in the level of neurotransmitters, cytosine's and hormones, whose actions induces structural and functional modifications in the central nervous system, the immune system and the endocrine system, which increases the risk of suffering major depression. Despite years of study, the biological basis of major depression and precise mechanisms of antidepressant efficacy remain unclear. The objective of the present review is to summarize the main conclusions of the clinical and experimental literature regarding to the etiology of major depressive disorder.

Activation of 5-HT receptors inhibits GABAergic transmission by pre-and post-synaptic mechanisms in layer II/III of the juvenile rat auditory cortex.

The specific mechanisms by which serotonin (5-HT) modulates synaptic transmission in the auditory cortex are still unknown. In this work, we used whole-cell recordings from layer II/III of pyramidal neurons in rat brain slices to characterize the influence of 5-HT on inhibitory synaptic activity in the auditory cortex after pharmacological blockade of excitatory glutamatergic transmission. We found that bath application of 5-HT (5 µM) reduced the frequency and amplitude of both spontaneous and miniature inhibitory postsynaptic currents (IPSCs), reduced the amplitude of evoked IPSCs, and enhanced facilitation of paired pulse ratio (PPR), suggesting presynaptic inhibition. To determine which the serotonin receptors were involved in this effect, we studied the influence of specific 5-HT receptor agonists and antagonists on É£-aminobutyric acid (GABA)ergic synaptic transmission. The inhibiting influence of 5-HT in the GABAergic synaptic activity was mimicked by using the selective agonists of the 5-HT1A and 5-HT2A receptors, 8(OH)-DPAT (10 µM) and DOI (10 µM), respectively; and it was prevented by their respective antagonists NAN-190 (1 µM) and ritanserin (1 µM). Furthermore, the application of the selective agonist of 5-HT1A receptors, 8-(OH)-DPAT (10 µM), produced PPR facilitation, while DOI application (5-HT2A agonist) did not change the PPR. Moreover, the 5-HT2A agonist reduced the amplitude of the IPSCs evoked by application of the selective GABA agonist, muscimol. These results suggest a presynaptic and postsynaptic reduction of GABAergic transmission mediated by 5-HT1A and 5-HT2A serotonergic receptors, respectively.