RESUMEN

The dorsal raphe nucleus (DRN) receives dopaminergic inputs from the ventral tegmental area (VTA). Also, the DRN contains a small population of cells that express dopamine (DRNDA neurons). However, the physiological role of dopamine (DA) in the DRN and its interaction with serotonergic (5-HT) neurons is poorly understood. Several works have reported moderate levels of D1, D2, and D3 DA receptors in the DRN. Furthermore, it was found that the activation of D2 receptors increased the firing of putative 5-HT neurons. Other studies have reported that D1 and D2 dopamine receptors can interact with glutamate NMDA receptors, modulating the excitability of different cell types. In the present work, we used immunocytochemical techniques to determine the kind of DA receptors in the DRN. Additionally, we performed electrophysiological experiments in brainstem slices to study the effect of DA agonists on NMDA-elicited currents recorded from identified 5-HT DRN neurons. We found that D2 and D3 but not D1 receptors are present in this nucleus. Also, we demonstrated that the activation of D2-like receptors increases NMDA-elicited currents in 5-HT neurons through a mechanism involving phospholipase C (PLC) and protein kinase C (PKC) enzymes. Possible physiological implications related to the sleep-wake cycle are discussed.

Asunto(s)

Núcleo Dorsal del Rafe , Receptores de Dopamina D2 , Receptores de N-Metil-D-Aspartato , Neuronas Serotoninérgicas , Animales , Núcleo Dorsal del Rafe/metabolismo , Núcleo Dorsal del Rafe/efectos de los fármacos , Receptores de Dopamina D2/metabolismo , Neuronas Serotoninérgicas/metabolismo , Neuronas Serotoninérgicas/efectos de los fármacos , Neuronas Serotoninérgicas/fisiología , Masculino , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de Dopamina D3/metabolismo , N-Metilaspartato/farmacología , N-Metilaspartato/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D1/agonistas , Agonistas de Dopamina/farmacología , Ratas , Fosfolipasas de Tipo C/metabolismo , Ratas Wistar

RESUMEN

Neuronal signals mediated by the biogenic amine serotonin (5-HT) underlie critical survival strategies across the animal kingdom. This investigation examined serotonin-like immunoreactive neurons in the cerebral ganglion of the panpulmonate snail Biomphalaria glabrata, a major intermediate host for the trematode parasite Schistosoma mansoni. Five neurons comprising the cerebral serotonergic F (CeSF) cluster of B. glabrata shared morphological characteristics with neurons that contribute to withdrawal behaviors in numerous heterobranch species. The largest member of this group, designated CeSF-1, projected an axon to the tentacle, a major site of threat detection. Intracellular recordings demonstrated repetitive activity and electrical coupling between the bilateral CeSF-1 cells. In semi-intact preparations, the CeSF-1 cells were not responsive to cutaneous stimuli but did respond to photic stimuli. A large FMRF-NH2-like immunoreactive neuron, termed C2, was also located on the dorsal surface of each cerebral hemiganglion near the origin of the tentacular nerve. C2 and CeSF-1 received coincident bouts of inhibitory synaptic input. Moreover, in the presence of 5-HT they both fired rhythmically and in phase. As the CeSF and C2 cells of Biomphalaria share fundamental properties with neurons that participate in withdrawal responses in Nudipleura and Euopisthobranchia, our observations support the proposal that features of this circuit are conserved in the Panpulmonata.NEW & NOTEWORTHY Neuronal signals mediated by the biogenic amine serotonin underlie critical survival strategies across the animal kingdom. This investigation identified a group of serotonergic cells in the panpulmonate snail Biomphalaria glabrata that appear to be homologous to neurons that mediate withdrawal responses in other gastropod taxa. It is proposed that an ancient withdrawal circuit has been highly conserved in three major gastropod lineages.

Asunto(s)

Biomphalaria , Neuronas Serotoninérgicas , Serotonina , Animales , Biomphalaria/fisiología , Biomphalaria/parasitología , Serotonina/metabolismo , Neuronas Serotoninérgicas/fisiología , Ganglios de Invertebrados/fisiología , Ganglios de Invertebrados/citología

RESUMEN

Air-breathing vertebrates undergo respiratory adjustments when faced with disturbances in the gas composition of the environment. In mammals, the medullary raphe nuclei are involved in the neuronal pathway that mediates the ventilatory responses to hypoxia and hypercarbia. We investigate whether the serotoninergic neurons of the medullary raphe nuclei of toads (Rhinella diptycha) play a functional role in respiratory control during resting conditions (room air), hypercarbia (5% CO2), and hypoxia (5% O2). The raphe nuclei were located and identified based on the location of the serotoninergic neurons in the brainstem. We then lesioned the medullary raphe (raphe pallidus, obscurus and magnus) with anti-SERT-SAP and measured ventilation in both control and lesioned groups and we observed that serotonin (5-HT) specific chemical lesions of the medullary raphe caused reduced respiratory responses to both hypercarbia and hypoxia. In summary, we report that the serotoninergic neurons of the medullary raphe of the cururu toad Rhinella diptycha participate in the chemoreflex responses during hypercarbia and hypoxia, but not during resting conditions. This current evidence in anurans, together with the available data in mammals, brings insights to the evolution of brain sites, such as the medullary raphe, involved in the ventilatory chemoreflex in vertebrates.

Asunto(s)

Bulbo Raquídeo/fisiología , Ventilación Pulmonar/fisiología , Núcleos del Rafe/fisiología , Respiración , Neuronas Serotoninérgicas/fisiología , Animales , Anuros , Femenino , Masculino

RESUMEN

Exposure to stress might influence pain sensitivity; however, little is known about whether post-traumatic stress disorder (PTSD)-like symptoms alter pain sensitivity and how it can happen. Male rats were exposed to the inescapable footshock paired with either social isolation or a control condition (not exposed to footshock but subjected to social isolation). After 7, 14, or 21 days, memory retention was evaluated. In the following three days, animals underwent the following tests: open-field, social interaction and formalin tests. Another group of animals were subjected to the object recognition test and to von Frey filaments. In other cohorts of animals, saline, fluoxetine, or desipramine were injected intrathecally and immunohistochemistry was performed to investigate whether PTSD-like symptoms alter the expression of c-Fos in serotonergic and noradrenergic neurons. Inescapable footshock induced the development of PTSD-like symptoms. Animals with PTSD-like symptoms showed an increase in the number of flinches in the formalin test and a reduction in mechanical threshold in the von Frey test at both retention intervals. The social interaction was negatively correlated with the nociceptive response in the formalin test. Fluoxetine or desipramine prevented the nociceptive response to chemical stimulus in the formalin test. In addition, in animals with PTSD-like symptoms, there was a reduction in c-Fos expression in serotonergic and noradrenergic neurons. Our results are important for the association of increased sensitivity to pain as one of the clinical manifestations that are present in the development of PTSD, and a possible treatment for increased pain sensitivity in male individuals with PTSD.

Asunto(s)

Dolor/fisiopatología , Trastornos por Estrés Postraumático/fisiopatología , Neuronas Adrenérgicas/metabolismo , Neuronas Adrenérgicas/fisiología , Animales , Conducta Animal , Fluoxetina/farmacología , Masculino , Norepinefrina/metabolismo , Dolor/metabolismo , Manejo del Dolor/psicología , Umbral del Dolor/efectos de los fármacos , Ratas , Ratas Wistar , Neuronas Serotoninérgicas/metabolismo , Neuronas Serotoninérgicas/fisiología , Conducta Social , Trastornos por Estrés Postraumático/metabolismo

RESUMEN

Breathing is regulated by a host of arousal and sleep-wake state-dependent neuromodulators to maintain respiratory homeostasis. Modulators such as acetylcholine, norepinephrine, histamine, serotonin (5-HT), adenosine triphosphate (ATP), substance P, somatostatin, bombesin, orexin, and leptin can serve complementary or off-setting functions depending on the target cell type and signaling mechanisms engaged. Abnormalities in any of these modulatory mechanisms can destabilize breathing, suggesting that modulatory mechanisms are not overly redundant but rather work in concert to maintain stable respiratory output. The present review focuses on the modulation of a specific cluster of neurons located in the ventral medullary surface, named retrotrapezoid nucleus, that are activated by changes in tissue CO2/H+ and regulate several aspects of breathing, including inspiration and active expiration.

Asunto(s)

Células Quimiorreceptoras/fisiología , Bulbo Raquídeo/fisiología , Receptores de Neurotransmisores/fisiología , Mecánica Respiratoria/fisiología , Adenosina Trifosfato/fisiología , Animales , Neuronas Colinérgicas/fisiología , Humanos , Bulbo Raquídeo/citología , Receptores Purinérgicos/fisiología , Respiración , Neuronas Serotoninérgicas/fisiología

RESUMEN

Organophosphates are among the most used pesticides. Particularly, chlorpyrifos (CPF) is responsible for a number of deleterious effects on brain development, which may program behavioral changes later in life. Here, we investigated whether a regimen of early low level CPF exposure that did not result in a significant inhibition of acetylcholinesterase (AChE) had deleterious effects on mood-related behaviors, as well as on cholinergic and serotonergic biomarkers in the mice brain. From the 3rd to 9th postnatal day (PN), male and female Swiss mice were subcutaneously injected with CPF. Mice were submitted to a battery of behavioral tests from PN60 to PN63: open field, elevated plus maze and forced swimming tests. The cholinergic and serotonergic biomarkers were assessed at PN10 and PN63. Our data indicated that early CPF exposure increased anxiety-like behavior in females and altered decision-making behavior in both sexes. Most biochemical alterations were sex-dependent and restricted to females. At PN10, CPF female mice showed increased serotonin and choline transporter binding in cerebral cortex. Distinctively, in adult females, the effects indicated a hypoactive state: CPF exposure reduced 5-HT1a receptor binding in cerebral cortex, as well as serotonin transporter binding and choline acetyltransferase activity in brainstem. Our results indicate that CPF exposure during the brain growth spurt deregulates serotonergic and cholinergic biomarkers. The effects are consistent with impaired synaptic function, may be related to long-term mood disorders and point out to higher female susceptibility.

Asunto(s)

Encéfalo/efectos de los fármacos , Cloropirifos/toxicidad , Insecticidas/toxicidad , Acetilcolinesterasa/metabolismo , Afecto/efectos de los fármacos , Animales , Animales Recién Nacidos , Conducta Animal/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Encéfalo/fisiopatología , Cloropirifos/administración & dosificación , Colina/metabolismo , Neuronas Colinérgicas/efectos de los fármacos , Neuronas Colinérgicas/fisiología , Femenino , Insecticidas/administración & dosificación , Masculino , Proteínas de Transporte de Membrana/metabolismo , Ratones , Modelos Animales , Receptores de Serotonina/metabolismo , Neuronas Serotoninérgicas/efectos de los fármacos , Neuronas Serotoninérgicas/fisiología

RESUMEN

The parafacial respiratory group (pFRG), located in the lateral aspect of the rostroventral lateral medulla, has been described as a conditional expiratory oscillator that emerges mainly in conditions of high metabolic challenges to increase breathing. The convergence of inhibitory and excitatory inputs to pFRG and the generation of active expiration may be more complex than previously thought. We hypothesized that the medullary raphe, a region that has long been described to be involved in breathing activity, is also responsible for the expiratory activity under hypercapnic condition. To test this hypothesis, we performed anatomical and physiological experiments in urethane-anesthetized adult male Wistar rats. Our data showed anatomical projections from serotonergic (5-HT-ergic) and GABAergic neurons of raphe magnus (RMg) and obscurus (ROb) to the pFRG region. Pharmacological inhibition of RMg or ROb with muscimol (60 pmol/30 nL) did not change the frequency or amplitude of diaphragm activity and did not generate active expiration. However, under hypercapnia (9-10% CO2), the inhibition of RMg or ROb increased the amplitude of abdominal activity, without changing the increased amplitude of diaphragm activity. Depletion of serotonergic neurons with saporin anti-SERT injections into ROb and RMg did not increase the amplitude of abdominal activity during hypercapnia. These results show that the presumably GABAergic neurons within the RMg and ROb may be the inhibitory source to modulate the activity of pFRG during hypercapnia condition.NEW & NOTEWORTHY Medullary raphe has been involved in the inspiratory response to central chemoreflex; however, these reports have never addressed the role of raphe neurons on active expiration induced by hypercapnia. Here, we showed that a subset of GABA cells within the medullary raphe directly project to the parafacial respiratory region, modulating active expiration under high levels of CO2.

Asunto(s)

Espiración/fisiología , Neuronas GABAérgicas/fisiología , Hipercapnia/fisiopatología , Bulbo Raquídeo/fisiología , Red Nerviosa/fisiología , Núcleos del Rafe/fisiología , Animales , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Wistar , Neuronas Serotoninérgicas/fisiología

RESUMEN

Ivermectin is a human and veterinary antiparasitic drug which is one of the most widely used in the world. Studies from our group have revealed several behavioral and neurochemical impairments induced by therapeutic doses of ivermectin in adult rats. However, the effects on juveniles remain unknown. Ivermectin has been prescribed for juvenile humans, pets and farm animals, which still show remarkable development and postnatal maturation and may be more susceptible to drug interventions. Hence, we studied the behavioral and neurochemical effects of two therapeutical doses (0.2 and 1.0 mg/kg) of ivermectin in juvenile rats. As it is underestimated in prescriptions, the stress factor was also studied. Ivermectin 1.0 mg/kg induced hyperlocomotion in juvenile rats. Association of 1.0 mg/kg ivermectin with stress induced hypolocomotion in rats. Ivermectin 1.0 mg/kg whether or not associated with stress exacerbated socialization of rats. Ivermectin did not induce anxiety-like behavior neither affected corticosterone levels of juvenile rats. The motor/exploratory behavioral findings induced by association of ivermectin and stress seem to be triggered after the increase in the striatal serotonergic system activity. Association of ivermectin with stress increased striatal dopamine levels, which increased (excessive) social play behavior. Our results suggest a review of the prescribed dose of ivermectin for juvenile humans and pets. Moreover, the stress factor should be considered for ivermectin medical prescriptions, since it may exacerbate behavioral and neurochemical disturbances.

Asunto(s)

Antiparasitarios/toxicidad , Ivermectina/toxicidad , Actividad Motora/efectos de los fármacos , Conducta Social , Animales , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/fisiología , Masculino , Ratas , Ratas Wistar , Neuronas Serotoninérgicas/efectos de los fármacos , Neuronas Serotoninérgicas/fisiología , Estrés Fisiológico/efectos de los fármacos

RESUMEN

Acute exposure to stress induces significant behavioural changes, while repeated exposure to the same stressor leads to the development of tolerance to stress. The development of tolerance appears to involve the serotonergic projections from the Median Raphe Nucleus (MnRN) to the dorsal Hippocampus (dH), since rats with lesions of this pathway does not develop tolerance to stress. Previous data from our laboratory showed that treatment with imipramine, a serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor, lead to the development of tolerance. However, it remains to be elucidated whether such tolerance involves the participation of the noradrenergic system, apart from the serotonergic projections. Therefore, the aim of this work was to investigate the behavioural and neurochemical effects of chronic treatment with desipramine (NA reuptake inhibitor) or fluoxetine (5-HT reuptake inhibitor) in chronically stressed rats with lesions of the serotonergic neurons of the MnRN. Male Wistar rats with or without lesion in the MnRN were submitted or not to acute (2 h) or chronic restraint (2 h/seven days) stress and tested in the elevated pus maze (EPM). Treatment with fluoxetine, desipramine (10 mg/kg) or saline was performed twice daily (12-12 h interval), for 7 consecutive days. EPM test was conducted 24 h after the treatment. Fluoxetine attenuated the anxiogenic-induced effect of lesion in chronically restrained rats, without changing serotonin and noradrenaline levels in the hippocampus of lesioned rats. A similar profile was also observed after treatment with desipramine. These results suggest that both the serotonergic and the noradrenergic systems are involved in the development of tolerance to chronic stress. Additionally, the integrity of the serotonergic pathway of the MnRN-dH is not essential for the anxiolytic-like effects of these drugs.

Asunto(s)

Núcleo Dorsal del Rafe/citología , Núcleo Dorsal del Rafe/lesiones , Norepinefrina/metabolismo , Neuronas Serotoninérgicas/fisiología , Serotonina/metabolismo , Estrés Psicológico , 5,7-Dihidroxitriptamina/farmacología , Análisis de Varianza , Animales , Desipramina/farmacología , Modelos Animales de Enfermedad , Tolerancia a Medicamentos , Fluoxetina/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Inhibidores de la Captación de Neurotransmisores/farmacología , Ratas , Ratas Wistar , Serotoninérgicos/farmacología , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Estrés Psicológico/patología

RESUMEN

BACKGROUND: In women, changes in estrogen levels may increase the incidence and/or symptomatology of depression and affect the response to antidepressant treatments. Estrogen therapy in females may provide some mood benefits as a single treatment or might augment clinical response to antidepressants that inhibit serotonin reuptake. OBJECTIVE: We analyzed the mechanisms of estradiol action involved in the regulation of gene expression that modulates serotonin neurotransmission implicated in depression. METHOD: Publications were identified by a literature search on PubMed. RESULTS: The participation of estradiol in depression may include regulation of the expression of tryptophan hydroxylase-2, monoamine oxidase A and B, serotonin transporter and serotonin-1A receptor. This effect is mediated by estradiol binding to intracellular estrogen receptor that interacts with estrogen response elements in the promoter sequences of tryptophan hydroxylase-2, serotonin transporter and monoamine oxidase-B. In addition to directly binding deoxyribonucleic acid, estrogen receptor can tether to other transcription factors, including activator protein 1, specificity protein 1, CCAAT/enhancer binding protein ß and nuclear factor kappa B to regulate gene promoters that lack estrogen response elements, such as monoamine oxidase-A and serotonin 1A receptor. CONCLUSION: Estradiol increases tryptophan hydroxylase-2 and serotonin transporter expression and decreases the expression of serotonin 1A receptor and monoamine oxidase A and B through the interaction with its intracellular receptors. The understanding of molecular mechanisms of estradiol regulation on the protein expression that modulates serotonin neurotransmission will be helpful for the development of new and more effective treatment for women with depression.

Asunto(s)

Depresión/fisiopatología , Estradiol/fisiología , Regulación de la Expresión Génica/fisiología , Neuronas Serotoninérgicas/fisiología , Animales , Depresión/genética , Depresión/metabolismo , Estradiol/metabolismo , Estradiol/farmacología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Neuronas Serotoninérgicas/efectos de los fármacos , Neuronas Serotoninérgicas/enzimología , Neuronas Serotoninérgicas/metabolismo , Serotonina/fisiología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Transmisión Sináptica/efectos de los fármacos , Triptófano Hidroxilasa/metabolismo

RESUMEN

The present study evaluated the possible antiallodynic effect induced by [6]-gingerol in rats with L5-L6 spinal nerve ligation (SNL). Moreover, we determined the possible mechanism underlying the antiallodynic effect induced by [6]-gingerol in neuropathic rats. The animals underwent L5-L6 SNL for the purpose of developing tactile allodynia. Tactile allodynia was measured with von Frey filaments. Intrathecal administration of [6]-gingerol reversed SNL-induced tactile allodynia. The [6]-gingerol-induced antiallodynic effect was prevented by the intrathecal administration of methiothepin (30 µg per rat; nonselective 5-hydroxytryptamine [5-HT] antagonist), WAY-100635 (6 µg per rat; selective 5-HT1A receptor antagonist), SB-224289 (5 µg per rat; selective 5-HT1B receptor antagonist), BRL-15572 (4 µg per rat; selective 5-HT1D receptor antagonist), and SB-659551 (6 µg per rat; selective 5-HT5A receptor antagonist), but naloxone (50 µg per rat; nonselective opioid receptor antagonist) did not prevent the [6]-gingerol-induced antiallodynic effect. Moreover, intrathecal administration of Nω-nitro-l-arginine methyl ester (100 µg per rat; nonselective nitric oxide [NO] synthase inhibitor), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10 µg per rat; inhibitor of guanylate cyclase), and glibenclamide (50 µg per rat; channel blocker of adenosine triphosphate [ATP]-sensitive K+ channels) prevented the [6]-gingerol-induced antiallodynic effect. These data suggest that the antiallodynic effect induced by [6]-gingerol is mediated by the serotoninergic system involving the activation of 5-HT1A/1B/1D/5A receptors, as well as the NO-cyclic guanosine monophosphate-ATP-sensitive K+ channel pathway but not by the opioidergic system.

Asunto(s)

Analgésicos/farmacología , Catecoles/farmacología , Alcoholes Grasos/farmacología , Hiperalgesia/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Adenosina Trifosfato/metabolismo , Animales , Compuestos de Bifenilo/farmacología , GMP Cíclico/metabolismo , Femenino , Guanosina Monofosfato/metabolismo , Hiperalgesia/metabolismo , Hiperalgesia/patología , Masculino , Neuralgia/metabolismo , Neuralgia/patología , Óxido Nítrico/metabolismo , Piperazinas/farmacología , Piperidonas/farmacología , Piridinas/farmacología , Ratas , Ratas Wistar , Receptores de Serotonina/metabolismo , Neuronas Serotoninérgicas/efectos de los fármacos , Neuronas Serotoninérgicas/fisiología , Compuestos de Espiro/farmacología

RESUMEN

The piperazine derivatives correspond to an extensive chemical class of compounds with numerous neuropharmacological activities, including antidepressant (e.g., nefazodone, trazodone) and anxiolytic (e.g., buspirone) properties. Therefore, aiming to identify a new antidepressant and antianxiety lead-compound, our group designed, synthesized, and investigated the effects of a new piperazine compound, namely, LQFM104, on the behavior of mice. Male albino Swiss mice were treated with LQFM104 prior to predictive behavioral tests as open field (OFT), elevated plus maze (EPM), forced swimming (FST), and tail suspension tests (TST). The participation of the serotonergic system was evaluated by pretreatment with a 5-HT1A antagonist receptor (WAY100635) and serotonin (5-HT) synthesis inhibitor (p-chlorphenylalanine, pCPA) before oral administration of LQFM104 and behavioral tests. The treatment with LQFM104 did not interfere with locomotor activity but revealed suggestive data of anxiolytic-like effects by the increase in the time spent in the center of the OFT. This activity was confirmed by the results obtained in the EPM, and it was abolished after pretreatment with WAY100635 and pCPA. The immobility time decreased in both the FST and TST. The antidepressant-like activity was completely abolished after WAY100635 pretreatment. Altogether, these data revealed that LQFM104 possesses anxiolytic and antidepressant-like properties in behavioral tests on mice, and these activities are possibly mediated, directly and/or indirectly, by serotonergic pathways.

Asunto(s)

Ansiolíticos/farmacología , Antidepresivos/farmacología , Piperazinas/farmacología , Receptor de Serotonina 5-HT1A/fisiología , Serotonina/fisiología , Animales , Ansiolíticos/química , Antidepresivos/química , Relación Dosis-Respuesta a Droga , Suspensión Trasera/métodos , Suspensión Trasera/psicología , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Piperazina , Piperazinas/química , Neuronas Serotoninérgicas/efectos de los fármacos , Neuronas Serotoninérgicas/fisiología , Antagonistas del Receptor de Serotonina 5-HT1/farmacología , Antagonistas de la Serotonina/farmacología

RESUMEN

Plasticity of neural circuits takes many forms and plays a fundamental role in regulating behavior to changing demands while maintaining stability. For example, during spinal cord development neurotransmitter identity in neurons is dynamically adjusted in response to changes in the activity of spinal networks. It is reasonable to speculate that this type of plasticity might occur also in mature spinal circuits in response to injury. Because serotonergic signaling has a central role in spinal cord functions, we hypothesized that spinal cord injury (SCI) in the fresh water turtle Trachemys scripta elegans may trigger homeostatic changes in serotonergic innervation. To test this possibility we performed immunohistochemistry for serotonin (5-HT) and key molecules involved in the determination of the serotonergic phenotype before and after SCI. We found that as expected, in the acute phase after injury the dense serotonergic innervation was strongly reduced. However, 30 days after SCI the population of serotonergic cells (5-HT+) increased in segments caudal to the lesion site. These cells expressed the neuronal marker HuC/D and the transcription factor Nkx6.1. The new serotonergic neurons did not incorporate the thymidine analog 5-bromo-2'-deoxyuridine (BrdU) and did not express the proliferating cell nuclear antigen (PCNA) indicating that novel serotonergic neurons were not newborn but post-mitotic cells that have changed their neurochemical identity. Switching towards a serotonergic neurotransmitter phenotype may be a spinal cord homeostatic mechanism to compensate for the loss of descending serotonergic neuromodulation, thereby helping the outstanding functional recovery displayed by turtles. The 5-HT1A receptor agonist (±)-8-Hydroxy-2-dipropylaminotetralin hydrobromide (8-OH-DPAT) blocked the increase in 5-HT+ cells suggesting 5-HT1A receptors may trigger the respecification process.

Asunto(s)

Neuronas Serotoninérgicas/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Regeneración de la Medula Espinal/fisiología , Médula Espinal/fisiopatología , Proteínas Anfibias/metabolismo , Animales , Neurogénesis/fisiología , Plasticidad Neuronal/fisiología , Receptor de Serotonina 5-HT1A/metabolismo , Neuronas Serotoninérgicas/patología , Médula Espinal/patología , Traumatismos de la Médula Espinal/patología , Factores de Transcripción/metabolismo , Tortugas

RESUMEN

Central chemoreceptors are primarily sensitive to changes in CO2/H+, and such changes lead to intense breathing activity. Medullary raphe and retrotrapezoid nucleus (RTN) neurons are candidates for central chemoreceptors because they are unusually pH sensitive. The pathophysiology of Parkinson's disease (PD) is related to the reduction of neurons in the substantia nigra pars compacta (SNpc) that express dopamine, although other neurons can also be degenerated in this pathology. In rodent models of PD, we showed an impairment of the hypercapnia ventilatory response due to a reduction in the number of RTN chemosensitive neurons. Here, we aimed to investigate if serotonine-expressing neurons in the Raphe pallidus/parapyramidal region (RPa/PPy) are also involved in the modulation of breathing during central chemoreception activation in a PD animal model. PD was induced in male Wistar rats with bilateral injection of 6-OHDA (6-hydroxydopamine; 24 µg/µl) into the striatum, which leads to a reduction in the catecholaminergic neurons of the SNpc by 89%. In PD animals, we noticed a reduction in the number of RPa neurons that project to the RTN, without a change in the number of hypercapnia-activated (7% CO2) raphe neurons. The PD animals that received injection of the toxin saporin anti-SERT into the RPA/PPy region did not show a further reduction of respiratory frequency (fR) or ventilation (VE) at rest or during hypercapnia challenge. These experiments demonstrate that serotonergic neurons of RPa/PPy are not involved in the breathing responses induced by central chemoreceptor activation in a PD animal model.

Asunto(s)

Células Quimiorreceptoras/fisiología , Núcleo Pálido del Rafe/fisiopatología , Trastornos Parkinsonianos/fisiopatología , Respiración , Animales , Dióxido de Carbono/metabolismo , Células Quimiorreceptoras/patología , Hipercapnia/patología , Hipercapnia/fisiopatología , Masculino , Vías Nerviosas/patología , Vías Nerviosas/fisiopatología , Núcleo Pálido del Rafe/patología , Oxidopamina , Trastornos Parkinsonianos/patología , Ratas Wistar , Neuronas Serotoninérgicas/patología , Neuronas Serotoninérgicas/fisiología

RESUMEN

The dorsal raphe nucleus (DRN) is a key structure of the endogenous pain inhibitory system. Although the DRN is rich in serotoninergic neurons, cholinergic neurons are also found in that nucleus. Both ictal and inter-ictal states are followed by post-ictal analgesia. The present study investigated the role of cholinergic mechanisms in postictal antinociceptive processes using microinjections of atropine and mecamylamine, muscarinic and nicotinic cholinergic receptor antagonists, respectively, in the DRN of rats. Intraperitoneal injection of pentylenetetrazole (PTZ) (at 64mg/kg) caused tonic and tonic-clonic seizures. The convulsive motor reactions were followed by an increase in pain thresholds, a phenomenon known as post-ictal analgesia. Pre-treatment of the DRN with atropine or mecamylamine at 1µg, 3µg and 5µg/0.2µL decreased the post-ictal antinociceptive phenomenon. The present results showed that the post-ictal analgesia was mediated by muscarinic and nicotinic cholinergic receptors in the DRN, a structure crucially involved in the neural network that organises post-ictal hypoalgesia.

Asunto(s)

Núcleo Dorsal del Rafe/fisiopatología , Umbral del Dolor/efectos de los fármacos , Receptores Muscarínicos/fisiología , Receptores Nicotínicos/fisiología , Transmisión Sináptica/fisiología , Acetilcolina/farmacología , Analgésicos/farmacología , Animales , Atropina/farmacología , Núcleo Dorsal del Rafe/efectos de los fármacos , Epilepsia Tónico-Clónica/metabolismo , Epilepsia Tónico-Clónica/fisiopatología , Neuronas GABAérgicas/metabolismo , Masculino , Mecamilamina/farmacología , Antagonistas Muscarínicos/farmacología , Antagonistas Nicotínicos/farmacología , Dimensión del Dolor/métodos , Umbral del Dolor/fisiología , Ratas , Ratas Wistar , Neuronas Serotoninérgicas/fisiología , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/fisiopatología , Transmisión Sináptica/efectos de los fármacos

RESUMEN

The dorsal raphe nucleus (DRN) contains large populations of serotonergic (5-HT) neurons. This nucleus receives GABAergic inhibitory afferents from many brain areas and from DRN interneurons. Both GABAergic and 5-HT DRN neurons express functional nicotinic acetylcholine receptors (nAChRs). Previous studies have demonstrated that nicotine increases 5-HT release and 5-HT DRN neuron discharge rate by stimulating postsynaptic nAChRs and by increasing glutamate and norepinephrine release inside DRN. However, the influence of nicotine on the GABAergic input to 5-HT DRN neurons was poorly investigated. Therefore, the aim of this work was to determine the effect of nicotine on GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) of 5-HT DRN neurons and the subtype of nAChR(s) involved in this response. Experiments were performed in coronal slices obtained from young Wistar rats. GABAergic sIPSCs were recorded from post hoc-identified 5-HT DRN neurons with the whole cell voltage patch-clamp technique. Administration of nicotine (1 µM) increased sIPSC frequency in 72% of identified 5-HT DRN neurons. This effect was not reproduced by the α4ß2 nAChR agonist RJR-2403 and was not influenced by TTX (1 µM). It was mimicked by the selective agonist for α7 nAChR, PNU-282987, and exacerbated by the positive allosteric modulator of the same receptor, PNU-120596. The nicotine-induced increase in sIPSC frequency was independent on voltage-gated calcium channels and dependent on Ca(2+)-induced Ca(2+) release (CICR). These results demonstrate that nicotine increases the GABAergic input to most 5-HT DRN neurons, by activating α7 nAChRs and producing CICR in DRN GABAergic terminals.

Asunto(s)

Núcleo Dorsal del Rafe/fisiología , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Neuronas Serotoninérgicas/fisiología , Receptor Nicotínico de Acetilcolina alfa 7/fisiología , Ácido gamma-Aminobutírico/fisiología , Animales , Señalización del Calcio , Núcleo Dorsal del Rafe/citología , Núcleo Dorsal del Rafe/efectos de los fármacos , Modelos Neurológicos , Ratas , Ratas Wistar , Neuronas Serotoninérgicas/efectos de los fármacos , Serotonina/metabolismo

RESUMEN

BACKGROUND: Suicidal behavior is a leading cause of injury and death worldwide. Several studies have provided a possible relationship between genetic factors and suicidal behavior. Also, these studies have shown evidence for altered serotonergic neural transmission in the pathogenesis of suicidal behavior. In addition, genes pertaining to the serotonergic system have been proposed as candidates to establish biological correlates between suicidal behavior and the serotonergic system. The most studied genes are SCL6A4, HTR2A, HTR2C, HTR1A, HTR1B, TPH-1, and TPH-2. To get a comprehensive understanding of the association with suicidal behavior we will conduct genotype assays studies in a Mexican population. METHODS/DESIGN: We will conduct a case-control study. The population sample will comprise adolescent and adult patients admitted for attempted of suicide and diagnosed by a psychiatrist. A peripheral blood sample will be taken from all the subjects (cases and controls). Genomic DNA from the leukocytes blood sample will be extracted. The genotypes of interest are distributed in the following genes: SCL6A4, HTR2A, HTR1A, HTR1B, HTR2C, TPH-2 and TPH-1. All the samples will be analyzed using a polymerase chain reaction (PCR) end-point method. We will evaluate the Hardy-Weinberg Equilibrium. The chi-squared test or Fisher's exact test will be used to compare genotype and allele frequencies between control and case groups. The Quanto 1.2 software will measure the sample size of the association. For all the association analyses the level of significance will be set at p = 0.05 and the confidence interval at 95%. DISCUSSION: Suicidal behavior has been increase in Mexico, principally in young population. Our study will demonstrate the association between serotoninergic genes and suicide behavior in Mexican population.

Asunto(s)

Predisposición Genética a la Enfermedad , Neuronas Serotoninérgicas/fisiología , Ideación Suicida , Transmisión Sináptica/genética , Adolescente , Adulto , Alelos , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , México , Persona de Mediana Edad , Receptores de Serotonina/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Triptófano Hidroxilasa/genética , Adulto Joven

RESUMEN

OBJECTIVES: There is a relationship between emotional disorders, obesity, and craving for carbohydrates. This relationship complicates the success of treatments aimed at combatting obesity, which is considered to be the epidemic of the twenty-first century. We conducted a review of the neurobiologic basis for carbohydrate craving, with the hope that this understanding will enable the design of more efficient therapeutic strategies. METHOD: We conducted a non-systematic literature search in PubMed using MeSH. RESULTS: Research on the basis of carbohydrate craving is varied, but may be grouped into five main areas: the serotonergic system, palatability and hedonic response, the motivational system, stress response systems, and gene-environment interaction. CONCLUSIONS: The models that integrate motivational systems with palatability and hedonic response studies are the ones that we believe can best explain both craving for carbohydrates and related addictive phenomena. Research has contributed to a greater understanding of the neurobiologic basis of carbohydrate craving. The latter, in turn, contributes to an understanding of the implications, challenges, and possible therapies that might be put in place to cope with this phenomenon.

Asunto(s)

Conducta Adictiva/psicología , Carbohidratos de la Dieta , Conducta Alimentaria/fisiología , Conducta Alimentaria/psicología , Trastornos de Alimentación y de la Ingestión de Alimentos/psicología , Obesidad/psicología , Afecto , Conducta Adictiva/fisiopatología , Trastornos de Alimentación y de la Ingestión de Alimentos/complicaciones , Interacción Gen-Ambiente , Humanos , Motivación , Obesidad/etiología , Neuronas Serotoninérgicas/fisiología , Serotonina/fisiología , Estrés Fisiológico

RESUMEN

The periaqueductal gray matter (PAG) consists in a brainstem structure rich in 5-hydroxytryptamine (5-HT) inputs related to the modulation of pain. The involvement of each of the serotonergic receptor subtypes found in PAG columns, such as the dorsomedial (dmPAG) and the ventrolateral (vlPAG) columns, regarding post-ictal antinociception have not been elucidated. The present work investigated the participation of the dmPAG and vlPAG columns in seizure-induced antinociception. Specifically, we studied the involvement of serotonergic neurotransmission in these columns on antinociceptive responses that follow tonic-clonic epileptic reactions induced by pentylenetetrazole (PTZ), an ionophore GABA-mediated Cl(-) influx antagonist. Microinjections of cobalt chloride (1.0 mM CoCl2 /0.2 µL) into the dmPAG and vlPAG caused an intermittent local synaptic inhibition and decreased post-ictal antinociception that had been recorded at various time points after seizures. Pretreatments of the dmPAG or the vlPAG columns with the nonselective serotonergic receptors antagonist methysergide (5.0 µg/0.2 µL) or intramesencephalic microinjections of ketanserin (5.0 µg/0.2 µL), a serotonergic antagonist with more affinity to 5-HT2A/2C receptors, decreased tonic-clonic seizure-induced antinociception. Both dmPAG and vlPAG treatment with either the 5-HT2A receptor selective antagonist R-96544 (10 nM/0.2 µL), or the 5-HT2C receptors selective antagonist RS-102221 (0.15 µg/0.2 µL) also decrease post-ictal antinociception. These findings suggest that serotonergic neurotransmission, which recruits both 5-HT2A and 5-HT2C serotonergic receptors in dmPAG and vlPAG columns, plays a critical role in the elaboration of post-ictal antinociception.

Asunto(s)

Nocicepción , Sustancia Gris Periacueductal/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2C/metabolismo , Animales , Masculino , Especificidad de Órganos , Sustancia Gris Periacueductal/fisiología , Ratas , Ratas Wistar , Convulsiones/inducido químicamente , Convulsiones/metabolismo , Convulsiones/fisiopatología , Neuronas Serotoninérgicas/metabolismo , Neuronas Serotoninérgicas/fisiología , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Transmisión Sináptica

RESUMEN

The medullary raphé is an important component of the central respiratory network, playing a key role in CO2 central chemoreception. However, its participation in hypoxic ventilatory responses is less understood. In the present study, we assessed the role of nucleus raphé obscurus (ROb), and specifically 5-HT neurons confined in the ROb, on ventilatory and thermoregulatory responses to hypoxia. Chemical lesions of the ROb were performed using either ibotenic acid (non-specific lesion; control animals received PBS) or anti-SERT-SAP (5-HT specific lesion; control animals received IgG-SAP). Ventilation (V˙E; whole body plethysmograph) and body temperature (Tb; data loggers) were measured during normoxia (21% O2, N2 balance) and hypoxia exposure (7% O2, N2 balance, 1h) in conscious adult rats. Ibotenic acid or anti-SERT-SAP-induced lesions did not affect baseline values of V˙E and Tb. Similarly, both lesion procedures did not alter the ventilatory or thermoregulatory responses to hypoxia. Although evidence in the literature suggests a role of the rostral medullary raphé in hypoxic ventilatory responses, under the present experimental conditions our data indicate that caudal medullary raphé (ROb) and its 5-HT neurons neither participate in the tonic maintenance of breathing nor in the ventilatory and thermal responses to hypoxia.

Asunto(s)

Regulación de la Temperatura Corporal/fisiología , Hipoxia/patología , Hipoxia/fisiopatología , Ventilación Pulmonar/fisiología , Núcleos del Rafe/patología , Neuronas Serotoninérgicas/fisiología , Animales , Anticuerpos/farmacología , Análisis de los Gases de la Sangre , Temperatura Corporal/efectos de los fármacos , Temperatura Corporal/fisiología , Regulación de la Temperatura Corporal/efectos de los fármacos , Recuento de Células , Modelos Animales de Enfermedad , Agonistas de Aminoácidos Excitadores/toxicidad , Ácido Iboténico/toxicidad , Masculino , Microinyecciones , Pletismografía Total , Ventilación Pulmonar/efectos de los fármacos , Proteínas de Unión al ARN/inmunología , Ratas , Ratas Wistar , Serotonina/metabolismo , Factores de Tiempo