Corticosteroids stimulate the amphibious behavior in mudskipper: potential role of mineralocorticoid receptors in teleost fish

It has long been held that cortisol, a glucocorticoid in many vertebrates, carries out both glucocorticoid and mineralocorticoid actions in teleost fish. However, 11-deoxycorticosterone (DOC) has been identified as a specific endogenous ligand for the teleostean mineralocorticoid receptor (MR). Furthermore, the expressions of MR mRNA are modest in the osmoregulatory organs, but considerably higher in the brain of most teleosts. These recent findings suggest that the mineralocorticoid system (DOC/MR) may carry out some behavioral functions in fish. To test this possibility, we examined the effects of cortisol and DOC administration in the amphibious behavior in mudskipper (Periophthalmus modestus) in vivo. It was found that mudskippers remained in the water for an increased period of time when they were immersed into 5 μM DOC or cortisol for 8 h. Additionally, an exposure to 25 μM DOC for 4 to 8 h caused a decreased migratory frequency of mudskippers to the water, reflected a tendency to remain in the water. It was further observed that after 8 h of intracerebroventricular (ICV) injection with 0.3 pmol DOC or cortisol the staying period in the water increased in fish. The migratory frequency was decreased after ICV DOC injection which indicated that fishes stayed in the water. Concurrent ICV injections of cortisol with RU486 [a specific glucocorticoid-receptor (GR) antagonist] inhibited only the partial effects of cortisol. Together with no changes in the plasma DOC concentrations under terrestrial conditions, these results indicate the involvement of brain MRs as cortisol receptors in the preference for an aquatic habitat of mudskippers. Although the role of GR signaling cannot be excluded in the aquatic preference, our data further suggest that the MR may play an important role in the brain dependent behaviors of teleost fish.     

Expressions of hippocampal mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) in the single-prolonged stress-rats

Post-traumatic stress disorder (PTSD) is a stress-related mental disorder caused by traumatic experience. Single-prolonged stress (SPS) is one of the animal models proposed for PTSD. Rats exposed to SPS showed enhanced inhibition of the hypothalamo-pituitary-adrenal (HPA) axis, which has been reliably reproduced in patients with PTSD. Mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) in the hippocampus regulate HPA axis by glucocorticoid negative feedback. Abnormalities in negative feedback are found in PTSD, suggesting that GR and MR might be involved in the pathophysiology of these disorders.In the present study, we performed immunohistochemistry and western blotting to examine the changes in hippocampal MR- and GR-expression after SPS. Immunohistochemistry revealed decreased MR- and GR-immunoreactivity (ir) in the CA1 of hippocampus in SPS animals. Change in GR sub-distribution was also observed, where GR-ir was shifted from nucleus to cytoplasm in SPS rats. Western blotting showed that SPS induced significantly decreased MR- and GR-protein in the whole hippocampus, although the degree of decreased expression of both receptors was different. Meanwhile, we also found the MR/GR ratio decreased in SPS rats. In general, SPS induced down-regulation of MR- and GR-expression. These findings suggest that MR and GR play critical roles in affecting hippocampal function. Changes in MR/GR ratio may be relevant for behavioral syndrome in PTSD.     

Unilateral intra-perilymphatic infusion of substance P enhances ipsilateral vestibulo-ocular reflex gains in the sinusoidal rotation test

Previous studies have reported localization of substance P (SP) within the inner ear and that SP exists abundantly within vestibular endorgans. While SP's functional role in the inner ear remains unclear, SP can act as a neuromodulator in the CNS and directly influences neuronal excitability. We hypothesized that SP might influence neuronal excitability within the vestibular periphery. The present study used the sinusoidal rotation test to investigate the influence of SP after its local application in the guinea pig unilateral inner ear. A tiny hole was made adjacent to the round window in the right ears of Hartley white guinea pigs that had normal tympanic membranes and Preyer reflexes. An osmotic pump infused SP (10⁻⁴ M, 10⁻³ M, and 10⁻² M), neurokinin-1 (NK-1) receptor antagonist (10⁻³ M) alone, or SP (10⁻³ M) + NK-1 receptor antagonist (10⁻³ M) through this hole, with rotation tests performed before, and 12 h and 24 h after the treatment. Results were used to calculate the vestibulo-ocular reflex (VOR) gains. After administration of 10⁻³ M and 10⁻² M SP, significant increases in the VOR gains were noted at 12 h after treatment, with these gains disappearing by 24 h after treatment. This increase was not observed when there was simultaneous NK-1 receptor antagonist administration. There were also no changes in the VOR gains noted after administration of 10⁻⁴ M SP or the NK-1 receptor antagonist alone. These results indicate the possibility that SP may act on vestibular endorgans as an excitatory factor via the NK-1 receptors.     

Inflammation of temporomandibular joint increases neural activity in rat vestibular nucleus

To determine whether the vestibular nuclei are affected by inflammation of temporomandibular joint (TMJ) region, we studied vestibular nucleus neural activity using two experimental groups: (1) normal saline 0.1 cm³ injection at right TMJ region, (2) 10% formalin 0.1 cm³ injection at right TMJ region. Neural activity after 24 hours was assessed by immunohistochemical staining with free-floating section at the level of interaural −1.30 mm to −2.00 mm for c-Fos. In inflammation group, formalin injection produced a bilateral increase in c-Fos at vestibular nucleus with ipsilesional side higher activity. In control group, expression of c-Fos protein was also observed in the vestibular nucleus (VN), especially MVN. But stain intensity of Fos-positive neurons was much weaker and mean number of c-Fos positive cells was fewer than inflammation group. This result suggests that there is a close neural connection between TMJ and vestibular nucleus, especially in case of inflammation.     

Modulation of histamine H3 receptor function by monovalent ions

Monovalent ions differently affect ligand binding to G protein-coupled receptors (GPCRs) by as yet poorly defined mechanisms. In particular, NaCl often decreases the affinity of agonists but increases it for antagonists. We examined the effect of various monovalent ions on human histamine H₃ receptor (hH₃R), co-expressed with mammalian G proteins (Gα_i1, Gα_i2, Gα_i3 or Gα_o1, and β₁γ₂ dimers, respectively) in Sf9 insect cell membranes, with respect to agonist binding and G protein activation. NaCl (100 mM) had no effect on affinity of the agonist [³H]N^α-methylhistamine ([³H]NAMH). In steady-state GTPase assays, the endogenous agonist histamine had a lower potency and the inverse agonist thioperamide had a higher potency, when NaCl (100 mM) was present. Monovalent ions reduced H₃R-regulated signalling in the order of efficacy Li⁺ ∼ Na⁺ ∼ K⁺ < Cl⁻ < Br⁻ < I⁻. NaCl had a stronger effect on basal hH3R-signalling when Gα_i3 was co-expressed. Asp80^2.50, a putative interaction site for Na⁺, was mutated to Asn80^2.50 (D2.50N-hH₃R). Strikingly, the mutation was unable to activate Gα_i3 at all. The effects can be explained by a model, where (i) monovalent ions as well as a charge-neutralizing mutation of Asp80^2.50 generally reduce the interaction of hH₃R with G proteins, (ii) monovalent anions increase the affinity of G proteins for GDP and thus, indirectly affect their interaction with hH₃R and, (iii) Asp80^2.50 is a key residue for hH₃R/Gα_i3-protein activation. The latter result suggests that hH₃R/G protein-coupling interfaces may differ even between closely related subunits.     

Antagonism of NMDA receptors by butanesulfonyl-homospermine guanidine and neuroprotective effects in in vitro and in vivo

The polyamine derivative BsHSPMG (butanesulfonyl-homospermine with guanidine group) was found to inhibit macroscopic currents strongly at heteromeric N-methyl-d-aspartate (NMDA) receptors (NR1/NR2A and NR1/NR2B) and Ca²⁺-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (homomeric glutamate receptor 1) receptors expressed in Xenopus laevis oocytes on voltage-clamp recording. The IC₅₀ values of BsHSPMG for NR1/NR2A, NR1/NR2B, NR1/NR2C, and NR1/NR2D receptors were 0.016, 0.021, 5.4, and 9.0 μM, respectively. BsHSPMG inhibited the activity of NR1/NR2A and NR1/NR2B receptors more strongly and did it for those of NR1/NR2C and NR1/NR2D receptors more weakly than a therapeutic drug of Alzheimer's disease, memantine. The inhibition by BsHSPMG was voltage-dependent, since it was prominent at −100 mV compared to that at −20 mV. Mutations including NR1 N616Q, E621Q, N650A, L655A, T807C, NR2B W559L, M562S, W607L, N616Q, and V620E, among others, reduced the inhibition by BsHSPMG, suggesting that BsHSPMG penetrates the channel pore of NMDA receptors deeply. The toxicity of BsHSPMG in neuroblastoma SH-SY5Y cells was much weaker than that of memantine. The effect of BsHSPMG was measured on the focal cerebral ischemia induced by occlusion (1 h) of the middle cerebral artery in mice. BsHSPMG applied before or after occlusion greatly reduced the volume of infarct in mice. These findings demonstrate that BsHSPMG penetrates the NMDA channel pore and exhibits neuroprotective effects against excitatory toxicity in mice.     

The role of Cɛ2, Cɛ3, and Cɛ4 domains in human and canine IgE and their contribution to FcɛRIα interaction

The C?2 and C?4 domains are considered as scaffolds, allowing C?3 domains to assume an appropriate orientation to interact with Fc?RI (0130 and 0050). Human/canine IgE chimeric antibodies were expressed to assess the nature of the contribution of C?2 and C?4 domains to bind to and induce target cell degranulation via Fc?RIα. Our results indicate that for (1) C?3 domains in IgE of canine and human origin are the only necessary region for binding to Fc?RIα. (2) The interaction of canine IgE with human sFc?RIα is significantly enhanced by contributions from both C?2 and C?4 domains of dog origin. (3) The canine/human IgE chimeric antibody construct rapidly dissociates from its the receptor when the canine C?2 and C?4 domains are replaced by the homologous human Fc domains which do not confer a conformation on the C?3 domain to facilitate stable interaction with canine Fc?RIα. Kinetic constants for the binding of this chimera to the soluble extracellular domain of the receptor indicate an approximate 120-fold decrease in the affinity for canine sFc?RIα (k_a = 5.30 × 10² M⁻¹ s⁻¹) and a 330-fold increase in the dissociation from canine sFc?RIα (K_D = 6.9 × 10⁻⁶ M⁻¹), compared to the wild type IgE kinetic constants (K_a = 6.30 × 10⁴ M⁻¹ s⁻¹; K_D = 2.1 × 10⁻⁸ M⁻¹). Although canine IgE does engage human Fc?RIα, canine C?2 and C?4 do not contribute to the high-affinity of interaction with human Fc?RIα. Upon replacement of human C?2 and C?4 domain by the canine homologues, human IgE C?3 only retains a low affinity for the human receptor, which shows that C?2 and C?4 domains in human IgE Fc contribute significantly to the interaction with its cognate receptor.     

Ingested soluble CD14 contributes to the functional pool of circulating sCD14 in mice

Soluble CD14 (sCD14) is a pattern recognition receptor and Toll-like co-receptor observed in human milk (5–26 μg/mL) and other bodily fluids such as blood (3 μg/mL). The most well defined role of sCD14 is to recognize lipopolysaccharide of Gram-negative bacteria and signal an immune response through Toll-like receptor 4 (TLR4). Previous research has shown ingested sCD14 to transfer from the gastrointestinal tract and into the blood stream in neonatal rats. The contribution of human milk sCD14 to circulating levels in the infant and the functionality of the protein, however, remained unknown. Using CD14^−/− mouse pups fostered to wild type (WT) mothers expressing sCD14 in their milk, we show herein that ingestion of sCD14 resulted in blood sCD14 levels up 0.16 ± 0.09 μg/mL. This represents almost one-third (26.7%) of the circulating sCD14 observed in WT pups fostered to WT mothers (0.60 ± 0.14 μg/mL). We also demonstrate that ingested-sCD14 transferred to the blood remains functional in its ability to recognize lipopolysaccharide as demonstrated by a significant increase in immune response (IL-6 and TNF-α) in CD14^−/− pups fostered to WT mothers in comparison to control animals (P = 0.002 and P = 0.007, respectively). Using human intestinal cells (Caco-2), we also observed a significant decrease in sCD14 transcytosis when TLR4 was knocked down (P < 0.001), suggesting sCD14 transfer involves TLR4. The bioavailability of human milk sCD14 established in this report confirms the importance of human milk proteins for the infant and demonstrates the need to improve infant formulas which are lacking in immune proteins such as sCD14.     

TLR2- and 4-independent immunomodulatory effect of high molecular weight components from Ascaris suum

Components of high molecular-weight (PI) obtained from Ascaris suum extract down-regulate the Th1/Th2-related immune responses induced by ovalbumin (OVA)-immunization in mice. Furthermore, the PI down-modulates the ability of dendritic cells (DCs) to activate T lymphocytes by an IL-10-mediated mechanism. Here, we evaluated the role of toll like receptors 2 and 4 (TLR2 and 4) in the modulatory effect of PI on OVA-specific immune response and the PI interference on DC full activation. An inhibition of OVA-specific cellular and humoral responses were observed in wild type (WT) or in deficient in TLR2 (TLR2^−/−) or 4 (TLR4^−/−) mice immunized with OVA plus PI when compared with OVA-immunized mice. Low expression of class II MHC, CD40, CD80 and CD86 molecules was observed in lymph node (LN) cells from WT, TLR2^−/− or TLR4^−/− mice immunized with OVA plus PI compared with OVA-primed cells. We also verified that PI was able to modulate the activation of DCs derived from bone marrow of WT, TLR2^−/− or TLR4^−/− mice induced in vitro by agonists of TLRs, as observed by a decreased expression of class II MHC and costimulatory molecules and by low secretion of pro-inflammatory cytokines. Its effect was accompanied by IL-10 synthesis. In this sense, the modulatory effect of PI on specific-immune response and DC activation is independent of TLR2 or TLR4.     

Effect of hyperthermia and anoxia on glucocorticoid and mineralocorticoid receptor expression in neonatal rat hippocampus

Brief periods of neonatal asphyxia are frequently observed. Within the CNS, the hippocampus is known to be particularly vulnerable to the damaging effects of hypoxia/ischaemia. The hippocampus contains the highest concentration of both mineralocorticoid (MR) and glucocorticoid (GR) receptors and the balance between MR/GR activation influences cell birth and death. MR occupation appears to promote prosurvival actions, while GR overactivation favours neurodegeneration. It has been widely recognized that core body temperature is a critical determinant of the severity of hypoxic–ischemic brain injury; indeed, hyperthermia exacerbates the degree of damage. Therefore, the aim of the present investigation was to study the effect of elevated body temperature in newborn rats under control conditions or during neonatal exposure to a critical anoxia, on changes of MR and GR mRNA expression in the rat hippocampus. 2-day-old rats were exposed to anoxia in 100% nitrogen atmosphere. Rectal temperature was kept at 33 °C (typical for the rat neonates), or elevated to a level typical for febrile (39 °C) adults. Control rats were exposed to atmospheric air under the respective thermal conditions. The changes in MR and GR mRNA expression in hippocampus were examined 24 h after exposure. Our data show that hyperthermia with or without added anoxia, causes induction of MR mRNA expression in neonatal rat hippocampus without any effect on GR mRNA expression. We suggest this elevation of MR plays an important role in modulating the survival of neurons in the injured hippocampus.     

Estrogen impairs glucocorticoid dependent negative feedback on the hypothalamic–pituitary–adrenal axis via estrogen receptor alpha within the hypothalamus

Numerous studies have established a link between individuals with affective disorders and a dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, most notably characterized by a reduced sensitivity to glucocorticoid negative (−) feedback. Furthermore there is a sex difference in the etiology of mood disorders with incidence in females being two to three times that of males, an association that may be a result of the influence of estradiol (E2) on HPA axis function. In these studies, we have examined the effect of E2 on glucocorticoid-mediated HPA axis (−) feedback during both the diurnal peak and the stress-induced rise in corticosterone (CORT). Young adult female Sprague–Dawley (SD) rats were ovariectomized (OVX) and 1 week later treated subcutaneous (s.c.) with oil or estradiol benzoate (EB) for 4 days. On the 4th day of treatment, animals were injected with a single dose of dexamethasone (DEX), or vehicle. EB treatment significantly increased the evening elevation in CORT and the stress-induced rise in CORT. In contrast, DEX treatment reduced the diurnal and stress induced rise in CORT and adrenocorticotropic hormone (ACTH), and this reduction was not apparent following co-treatment with EB. To determine a potential site of E2's action, female SD rats were OVX and 1 week later, wax pellets containing E2, the estrogen receptor beta (ERβ) agonist diarylpropionitrile (DPN), or the estrogen receptor alpha (ERα) agonist propylpyrazoletriol (PPT), was implanted bilaterally and dorsal to the paraventricular nucleus of the hypothalamus (PVN). Seven days later, animals were injected s.c. with a single dose of DEX, or vehicle to test for glucocorticoid-dependent (−) feedback. Results show that E2 and PPT increased, while DPN decreased the diurnal peak and stress-induced CORT and ACTH levels as compared to controls. Furthermore, E2 and PPT impaired the ability of DEX to inhibit both the diurnal and the stress-induced rise in CORT and ACTH, whereas DPN had no effect. Neuronal activation was measured by c-fos mRNA expression within the PVN following restraint. E2 and PPT increased c-fos mRNA, and impaired the normal DEX suppression of neuronal activation in the PVN. Taken together, these data indicate that estradiol causes a dysregulation of HPA axis (−) feedback as evidenced by the inability of DEX to suppress diurnal and stress-induced CORT and ACTH secretion. Additionally, the ability of E2 to inhibit glucocorticoid (–) feedback occurs specifically via ERα acting at the level of the PVN.     

Experimental acute myocardial infarction in rats: HIF-1α, caspase-3, erythropoietin and erythropoietin receptor expression and the cardioprotective effects of two different erythropoietin doses

The cardioprotective effects of two different doses of erythropoietin administration were analyzed in rats with experimental myocardial infarction. None, saline, standard-dose (5000 U kg⁻¹) and high-dose (10,000 U kg⁻¹) of human recombinant erythropoietin alpha were administered intraperitoneally in Wistar rats with myocardial infarction induced by coronary artery ligation. Infarct sizes measured after triphenyltetrazolium chloride staining, levels of biochemical markers, histopathology examined by light and electron microscopy, and immunohistochemical expressions of erythropoietin, erythropoietin receptor, hypoxia inducible factor-1α and caspase-3, were analyzed. Lower scores of infarction and hemorrhage, lower number of macrophages and higher score of vascularization surrounding the infarct area were observed in the erythropoietin administered groups (p < 0.05). Erythropoietin administration after myocardial infarction reduced the area of infarction and hemorrhage. There were hypoxia inducible factor-1α and caspase-3 expressions in the marginal area, and erythropoietin and erythropoietin receptor expression in both marginal and normal areas (p < 0.001). Vascularization, erythropoietin expression in the normal area and vascular erythropoietin expression were positively correlated with human erythropoietin levels. The cardioprotective effects of erythropoietin treatment were independent of endogenous erythropoietin/erythropoietin receptor activity. Moreover exogenous erythropoietin treatment did not suppress endogenous erythropoietin. Erythropoietin administration after myocardial infarction reduced caspase 3 expression (apoptotic activity) and induced neovascularization around the infarct area. Higher erythropoietin administration did not provide an additional benefit over the standard-dose in myocardial protection.     

Opposing roles of glucocorticoid receptor and mineralocorticoid receptor in trimethyltin-induced cytotoxicity in the mouse hippocampus

The organotin trimethyltin (TMT) is known to cause neuronal degeneration in the murine brain. Earlier studies indicate that TMT-induced neuronal degeneration is enhanced by adrenalectomy and prevented by exogenous glucocorticoid. The aim of this study was to investigate the regulation of TMT neuroxicity by corticosterone receptors including type I (mineralocorticoid receptor, MR) and type II (glucocorticoid receptor, GR) in adult mice. The systemic injection of TMT at the dose of 2.0 or 2.8 mg/kg produced a marked elevation in the level of plasma corticosterone that was both dose and time dependent. The MR agonist aldosterone had the ability to exacerbate TMT cytotoxicity in the dentate granule cell layer, whereas its antagonist spironolactone protected neurons from TMT cytotoxicity there. In contrast, the GR antagonist mifepristone exacerbated the TMT cytotoxicity. Taken together, our data suggest TMT cytotoxicity is oppositely regulated by GR and MR signals, being exacerbated by MR activation in adult mice.     

Effect of neonatal respiratory infection on adult BALB/c hippocampal glucocorticoid and mineralocorticoid receptors

The current study investigated the effects of neonatal infection with Chlamydia muridarum bacteria on glucocorticoid (GR) and mineralocorticoid (MR) receptors in the adult mouse hippocampus. In male adults infected at birth, circulating corticosterone was significantly increased when compared to same sex controls; while neonatal infection resulted in female adults with significantly increased GR mRNA compared to same sex controls. When comparing males and females after neonatal infection, males had significantly less GR protein than females. Interestingly, after control treatment, males had significantly more GR mRNA, MR mRNA, and GR protein with significantly lower corticosterone than females. Neonatal respiratory infection significantly impacts adult hippocampal GR and MR, and circulating corticosterone in a sex-specific manner potentially altering stress responsivity.     

Influence of extremely low frequency magnetic fields on Ca signaling and NMDA receptor functions in rat hippocampus

Extremely low frequency (ELF < 300 Hz) electromagnetic fields affect several neuronal activities including memory. Because ELF magnetic fields cause altered Ca²⁺ homeostasis in neural tissues, we examined their influence on Ca²⁺ signaling enzymes in hippocampus and related them with NMDA receptor functions. Hippocampal regions were obtained from brains of 21-day-old rats that were exposed for 90 days to 50 Hz magnetic fields at 50 and 100 μT intensities. In comparison to controls, ELF exposure caused increased intracellular Ca²⁺ levels concomitant with increased activities of Ca²⁺-dependent protein kinase C (PKC), cAMP-dependent protein kinase and calcineurin as well as decreased activity of Ca²⁺–calmodulin-dependent protein kinase in hippocampal regions. Simultaneous ligand-binding studies revealed decreased binding to N-methyl-d-aspartic acid (NMDA) receptors. The combined results suggest that perturbed neuronal functions caused by ELF exposure may involve altered Ca²⁺ signaling events contributing to aberrant NMDA receptor activities.     

Killing of immature CD4+CD8+ thymocytes in vivo by anti-CD3 or 5′-(N-ethyl)-carboxamido-adenosine is blocked by glucocorticoid receptor antagonist RU-486

Negative selection in thymus occurs by apoptosis in CD4⁺CD8¹ cells. These immature thymocytes are readily killed, both in vitro and in vivo, by glucocorticoid treatment. Increased levels of intracellular cAMP in vitro also induce apoptosis of thymocytes and T cell receptor (TcR) stimulation potentiate cAMP responses through receptors linked to adenylic cyclase. Presently, we have tested the possibility that TcR-mediated apoptosis in vivo may require the glucocorticoid receptor (GR) as a downstream, intracellular mediator. Use of the GR antagonist RU-486, 24 h before and simultaneous with, anti-CD3 or 5′-(N-ethyl)-carboxamide-adenosine (NECA) treatment, resulted in a selective inhibition of CD4⁺CD8⁺ thymocyte death. In addition, a low dose of glucocorticoid potentiated thymocyte death induced by anti-CD3 monoclonal antibodies. These data support a model in which thymic negative selection depends on a defined set of transduction signals which potentiate the GR to become responsive to endogenous levels of glucocorticoid.     

Beneficial effects of cannabinoids (CB) in a murine model of allergen-induced airway inflammation: role of CB1/CB2 receptors

The endocannabinoid system (ECS) consists of two cannabinoid (CB) receptors, namely CB₁ and CB₂ receptor, and their endogenous (endocannabinoids) and exogenous (cannabinoids, e.g. delta-9-tetrahydrocannabinol (THC)) ligands which bind to these receptors. Based on studies suggesting a role of THC and the ECS in inflammation, the objective of this study was to examine their involvement in type I hypersensitivity using a murine model of allergic airway inflammation. THC treatment of C57BL/6 wildtype mice dramatically reduced airway inflammation as determined by significantly reduced total cell counts in bronchoalveolar lavage (BAL). These effects were greatest when mice were treated during both, the sensitization and the challenge phase. Furthermore, systemic immune responses were significantly suppressed in mice which received THC during sensitization phase. To investigate a role of CB_1/2 receptors in this setting, we used pharmacological blockade of CB₁ and/or CB₂ receptors by the selective antagonists and moreover CB₁/CB₂ receptor double-knockout mice (CB₁^−/−/CB₂^−/−) and found neither significant changes in the cell patterns in BAL nor in immunoglobulin levels as compared to wildtype mice. Our results indicate that the activation of the ECS by applying the agonist THC is involved in the development of type I allergies. However, CB₁/CB₂ receptor-independent signalling seems likely in the observed results.     

Hypothalamic serotonin-1A receptor binding measured by PET predicts the plasma level of dehydroepiandrosterone sulfate in healthy women

Serotonin modulates the activity of the hypothalamic–pituitary–adrenal (HPA) axis particularly via the serotonin-1A receptor (5-HT_1A). Therefore, the rationale of this positron emission tomography (PET) study was to investigate the influence of the 5-HT_1A receptor distribution in the human brain on plasma levels of dehydroepiandrosterone sulfate (DHEAS) and cortisol in vivo. Eighteen healthy female were measured with PET and the selective 5-HT_1A receptor radioligand [carbonyl-¹¹C]WAY-100635. Nine a priori defined brain regions (hypothalamus, orbitofrontal cortex, amygdala, hippocampus, anterior and posterior cingulate cortices, dorsal raphe nucleus, retrosplenial cortex, and insula) and the cerebellum (reference region) were delineated on coregistered MR images. DHEAS and cortisol plasma levels were collected by blood sampling in the morning of the PET day. Linear regression analysis of DHEAS plasma level as dependent variable and hypothalamic 5-HT_1A receptor binding potential (BP) as independent variable showed a highly significant association (r = .691, p = .002). The hypothalamic 5-HT_1A BP predicted 47.7% of the variability in DHEAS plasma levels. Regressions were borderline significant (p < .01, Bonferroni corrected threshold <.0056) between 5-HT_1A BP in the anterior cingulate and orbitofrontal cortices and free cortisol levels. No significant associations between DHEAS or cortisol and the 5-HT_1A receptor BP in other investigated brain regions were found. In conclusion, the serotonergic system may influence the DHEAS plasma level by modulating CRH and ACTH release via hypothalamic 5-HT_1A receptors as reported for cortisol before. As disturbances of the HPA axis as well as changes of the 5-HT_1A receptor distribution have been reported in affective disorders, future studies should focus on these interactions.