RESUMEN
Mast cell activation and degranulation can result in the release of various chemical mediators, such as histamine and cytokines, which significantly affect sleep. Mast cells also exist in the central nervous system (CNS). Since up to 50% of histamine contents in the brain are from brain mast cells, mediators from brain mast cells may significantly influence sleep and other behaviors. In this study, we examined potential involvement of brain mast cells in sleep/wake regulations, focusing especially on the histaminergic system, using mast cell deficient (W/W(v)) mice. No significant difference was found in the basal amount of sleep/wake between W/W(v) mice and their wild-type littermates (WT), although W/W(v) mice showed increased EEG delta power and attenuated rebound response after sleep deprivation. Intracerebroventricular injection of compound 48/80, a histamine releaser from mast cells, significantly increased histamine levels in the ventricular region and enhanced wakefulness in WT mice, while it had no effect in W/W(v) mice. Injection of H1 antagonists (triprolidine and mepyramine) significantly increased the amounts of slow-wave sleep in WT mice, but not in W/W(v) mice. Most strikingly, the food-seeking behavior observed in WT mice during food deprivation was completely abolished in W/W(v) mice. W/W(v) mice also exhibited higher anxiety and depression levels compared to WT mice. Our findings suggest that histamine released from brain mast cells is wake-promoting, and emphasizes the physiological and pharmacological importance of brain mast cells in the regulation of sleep and fundamental neurobehavior.
Asunto(s)
Conducta Animal/fisiología , Encéfalo/metabolismo , Encéfalo/fisiología , Liberación de Histamina/fisiología , Histamina/metabolismo , Mastocitos/fisiología , Vigilia/fisiología , Animales , Electroencefalografía/métodos , Masculino , Mastocitos/metabolismo , Ratones , Sueño/fisiología , Privación de Sueño/metabolismo , Privación de Sueño/fisiopatologíaRESUMEN
Reduced cerebrospinal fluid (CSF) histamine levels were found in human hypersomnia. To evaluate the functional significance of changes in CSF histamine levels, we measured the levels in rats across 24h, after the administration of wake-promoting compounds modafinil, amphetamine, and thioperamide, and after sleep deprivation and food deprivation. Thioperamide significantly increased CSF histamine levels with little effects on locomotor activation. Both modafinil and amphetamine markedly increased the locomotor activity, but had no effects on histamine. The levels are high during active period and are markedly elevated by sleep deprivation, but not by food deprivation. Our study suggests that CSF histamine levels in rats reflect the central histamine neurotransmission and vigilance state changes, providing deeper insight into the human data.
Asunto(s)
Encéfalo/metabolismo , Trastornos de Somnolencia Excesiva/líquido cefalorraquídeo , Histamina/líquido cefalorraquídeo , Sueño/fisiología , Transmisión Sináptica/fisiología , Vigilia/fisiología , Anfetamina/farmacología , Animales , Compuestos de Bencidrilo/farmacología , Encéfalo/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Ritmo Circadiano/efectos de los fármacos , Ritmo Circadiano/fisiología , Trastornos de Somnolencia Excesiva/fisiopatología , Privación de Alimentos/fisiología , Masculino , Modafinilo , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Piperidinas/farmacología , Ratas , Ratas Sprague-Dawley , Sueño/efectos de los fármacos , Privación de Sueño/metabolismo , Privación de Sueño/fisiopatología , Vigilia/efectos de los fármacosAsunto(s)
Inhibidores de Captación Adrenérgica/farmacología , Encéfalo/efectos de los fármacos , Ciclopropanos/farmacología , Norepinefrina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Serotonina/metabolismo , Hormona Adrenocorticotrópica/sangre , Adulto , Encéfalo/metabolismo , Ciclopropanos/administración & dosificación , Método Doble Ciego , Esquema de Medicación , Humanos , Masculino , Persona de Mediana Edad , Milnaciprán , Paroxetina/administración & dosificación , Valores de Referencia , Factores de TiempoRESUMEN
Peripheral administration of cholecystokinin (CCK)-8 selectively activates oxytocin (OXT)-secreting neurons in the supraoptic (SON) and the paraventricular nuclei (PVN) with the elevation of plasma OXT level in rats. We examined the effects of intravenous (iv) administration of CCK-8 on the neuronal activity of hypothalamic OXT-secreting neurons and plasma OXT level in Otsuka Long-Evans Tokushima Fatty (OLETF) rats that have a congenital defect in the expression of the CCK-A receptor gene. In situ hybridization histochemistry (ISH) for c-fos mRNA revealed that the expression of the c-fos gene was not induced in the SON, the PVN, the nucleus of the tractus solitarius (NTS) and the area postrema (AP) 30 min after iv administration of CCK-8 (20 and 40 microg/kg) in OLETF rats. In Long-Evans Tokushima Otsuka (LETO) rats (controls), c-fos mRNA was detected abundantly in those nuclei 30 min after iv administration of CCK-8 (20 microg/kg). Immunohistochemistry for c-fos protein (Fos) showed that the distributions of Fos-like immunoreactivity (LI) were identical to the results obtained from ISH. Dual immunostaining for OXT and Fos revealed that Fos-LI was mainly observed in OXT-secreting neurons in the SON and the PVN of LETO rats 90 min after iv administration of CCK-8 (20 microg/kg). Radioimmunoassay for OXT and arginine vasopressin (AVP) showed that iv administration of CCK-8 did not cause significant change in the plasma OXT and AVP levels in OLETF rats, while iv administration of CCK-8 caused a significant elevation of plasma OXT level without changing the plasma AVP level in LETO rats. These results suggest that peripheral administration of CCK-8 may selectively activate the hypothalamic OXT-secreting neurons and brainstem neurons through CCK-A receptor in rats.
Asunto(s)
Colecistoquinina/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Oxitocina/metabolismo , Fragmentos de Péptidos/farmacología , Receptor de Colecistoquinina A/deficiencia , Animales , Animales Modificados Genéticamente , Arginina Vasopresina/sangre , Proteína C-Reactiva/efectos de los fármacos , Proteína C-Reactiva/metabolismo , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica/fisiología , Hipotálamo/citología , Hibridación in Situ/métodos , Masculino , Proteínas del Tejido Nervioso/efectos de los fármacos , Proteínas del Tejido Nervioso/metabolismo , Proteínas Oncogénicas v-fos/genética , Proteínas Oncogénicas v-fos/metabolismo , Radioinmunoensayo/métodos , Ratas , Ratas Endogámicas OLETF , Factores de TiempoRESUMEN
We examined the effects of intracerebroventricular (i.c.v.) administration of adrenomedullin 2 (AM2) on plasma oxytocin (OXT) and arginine vasopressin (AVP) levels in conscious rats. Plasma OXT levels were markedly increased 5 min after i.c.v. administration of AM2 (1 nmol/rat) compared with vehicle and remained elevated in samples taken at 10, 15, 30, and 60 min. By contrast, plasma AVP levels were not significantly elevated in samples taken between 5 and 180 min after i.c.v. administration of AM2 except at the 30-min time point. Fos-like immunoreactivity (Fos-LI) was observed in various brain areas, including the paraventricular (PVN) and the supraoptic nuclei (SON) after i.c.v. administration of AM2 (2 nmol/rat) in conscious rats (measured at 90 min post-AM2 infusion). Dual immunostaining for OXT/Fos and AVP/Fos showed that OXT-LI neurons predominantly exhibited nuclear Fos-LI compared with AVP-LI neurons in the PVN and the SON. In situ hybridization histochemistry showed that i.c.v. administration of AM2 (0.2, 1, and 2 nmol/rat) caused marked induction of the expression of the c-fos gene in the PVN and the SON. This induction was significantly reduced by pretreatment with both the calcitonin gene-related peptide (CGRP) antagonist CGRP-(8-37) (3 nmol/rat) and the AM receptor antagonist AM-(22-52) (27 nmol/rat). These results suggest that centrally administered AM2 mainly activates OXT-secreting neurons in the PVN and the SON, at least in part through the CGRP and/or AM receptors with marked elevation of plasma OXT levels in conscious rats.
Asunto(s)
Neuronas/efectos de los fármacos , Neuropéptidos/farmacología , Oxitocina/sangre , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Núcleo Supraóptico/efectos de los fármacos , Adrenomedulina , Animales , Arginina Vasopresina/antagonistas & inhibidores , Arginina Vasopresina/sangre , Arginina Vasopresina/metabolismo , Péptido Relacionado con Gen de Calcitonina/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Inmunohistoquímica , Hibridación in Situ , Inyecciones Intraventriculares , Masculino , Neuronas/metabolismo , Oxitocina/antagonistas & inhibidores , Oxitocina/metabolismo , Núcleo Hipotalámico Paraventricular/citología , Núcleo Hipotalámico Paraventricular/metabolismo , Fragmentos de Péptidos/farmacología , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Proteínas Proto-Oncogénicas c-fos/genética , Ratas , Ratas Wistar , Núcleo Supraóptico/citología , Núcleo Supraóptico/metabolismoRESUMEN
Lithium addition to neuroleptic treatment brought about some improvement in 6 schizophrenic inpatients. In 3 of them, however, enhancement of daily activity did not parallel improvement in psychiatric symptoms. This suggests that lithium addition may enhance daily activity independently of psychiatric symptoms, and that lithium effects should also be assessed from the viewpoint of daily activity.