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PubMed2006

Regulation of osteoclast function and bone mass by RAGE.

The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily that has multiple ligands and is implicated in the pathogenesis of various diseases, including diabetic complications, neurodegenerative disorders, and inflammatory responses. However, the role of RAGE in normal physiology is largely undefined. Here, we present evidence for a role of RAGE in osteoclast maturation and function, which has consequences for bone remodeling. Mice lacking RAGE had increased bone mass and bone mineral density and decreased bone resorptive activity in vivo. In vitro-differentiated RAGE-deficient osteoclasts exhibited disrupted actin ring and sealing zone structures, impaired maturation, and reduced bone resorptive activity. Impaired signaling downstream of alphavbeta3 integrin was observed in RAGE(-/-) bone marrow macrophages and precursors of OCs. These results demonstrate a role for RAGE in osteoclast actin cytoskeletal reorganization, adhesion, and function, and suggest that the osteosclerotic-like phenotype observed in RAGE knockout mice is due to a defect in osteoclast function.

Actins↗
PubMed2004

Antagonism of RAGE suppresses peripheral nerve regeneration.

Axotomy of peripheral nerve triggers events that coordinate a limited inflammatory response to axonal degeneration and initiation of neurite outgrowth. Inflammatory and neurite outgrowth-promoting roles for the receptor for advanced glycation end products (RAGE) have been suggested, so we tested its role in peripheral nerve regeneration. Analysis of immunohistochemical localization of RAGE by confocal microscopy revealed that RAGE was expressed in axons and infiltrating mononuclear phagocytes upon unilateral sciatic nerve crush in mice. Administration of soluble RAGE, the extracellular ligand binding domain of RAGE, or blocking F(ab')2 fragments of antibodies raised to either RAGE or its ligands, S100/calgranulins or amphoterin, reduced functional recovery as assessed by motor and sensory nerve conduction velocities and sciatic functional index and reduced regeneration, as assessed by myelinated fiber density after acute crush of the sciatic nerve. In parallel, in mice subjected to RAGE blockade, decreased numbers of mononuclear phagocytes infiltrated the distal nerve segments after crush. These findings provide the first evidence of an innate function of the ligand/RAGE axis and suggest that RAGE plays an important role in regeneration of the peripheral nervous system.

Animals↗
PubMed2004

RAGE modulates peripheral nerve regeneration via recruitment of both inflammatory and axonal outgrowth pathways.

Axotomy of peripheral nerve stimulates events in multiple cell types that initiate a limited inflammatory response to axonal degeneration and simultaneous outgrowth of neurites into the distal segments after injury. We found that pharmacological blockade of RAGE impaired peripheral nerve regeneration in mice subjected to RAGE blockade and acute crush of the sciatic nerve. As our studies revealed that RAGE was expressed in axons and in infiltrating mononuclear phagocytes upon injury, we tested the role of RAGE in these distinct cell types on nerve regeneration. Transgenic mice expressing signal transduction-deficient RAGE in mononuclear phagocytes or peripheral neurons were generated and subjected to unilateral crush injury to the sciatic nerve. Transgenic mice displayed decreased functional and morphological recovery compared with littermate controls, as assessed by motor and sensory conduction velocities; and myelinated fiber density. In double transgenic mice expressing signal transduction deficient RAGE in both mononuclear phagocytes and peripheral neurons, regeneration was even further impaired, suggesting the critical interplay between RAGE-modulated inflammation and neurite outgrowth in nerve repair. These findings suggest that RAGE signaling in inflammatory cells and peripheral neurons plays an important role in plasticity of the peripheral nervous system.

Animals↗
PubMed2003

Glucose, glycation, and RAGE: implications for amplification of cellular dysfunction in diabetic nephropathy.

Receptor for advanced glycation endproducts (RAGE) is a multi-ligand member of the immunoglobulin superfamily of cell surface molecules. Driven by rapid accumulation and expression of key ligands such as advanced glycation endproducts (AGE) and S100/calgranulins in diabetic tissues, upregulation and activation of RAGE magnifies cellular perturbation in tissues affected by hyperglycemia, such as the large blood vessels and the kidney. In the diabetic glomerulus, RAGE is expressed principally by glomerular visceral epithelial cells (podocytes). Blockade of RAGE in the hyperglycemic db/db mouse suppresses functional and structural alterations in the kidney, in the absence of alterations in blood glucose. Recent studies in homozygous RAGE null mice support a key role for RAGE in glomerular perturbation in diabetes. Importantly, beyond diabetes, studies in other settings of glomerulopathies support a critical RAGE-dependent pathway in podocytes linked to albuminuria, mesangial expansion, and glomerular sclerosis. A new paradigm is proposed in glomerular injury, and it is suggested that blockade of the RAGE axis may provide a novel means to prevent irreparable glomerular injury in diabetes and other sclerosing glomerulopathies.

Animals↗
PubMed2003

The AGE-RAGE system and diabetic nephropathy.

As is diabetes itself, diabetic vasculopathy is a multifactor disease. Studies revealed advanced glycation end products (AGE) as the major environmental account for vascular cell derangement characteristic of diabetes and the receptor for AGE (RAGE) as the major genic factor that responds to them. AGE fractions that caused the vascular derangement were proved to be RAGE ligands. When made diabetic, RAGE transgenic mice exhibited the exacerbation of the indices of nephropathy and retinopathy, and this was prevented by the inhibition of AGE formation. Extracellular signals and nuclear factors that induce the transcription of human RAGE gene were also identified, which would be regarded as risk factors of diabetic complications. Through an analysis of vascular polysomal poly(A)(+)RNA, a novel splice variant coding for a soluble RAGE protein was found and was named endogenous secretory RAGE. Endogenous secretory RAGE was able to capture AGE ligands and to neutralize the AGE action on endothelial cells, suggesting that this variant has a potential to protect blood vessels from diabetes-induced injury. The AGE-RAGE system, therefore, should be a candidate molecular target for overcoming this life- and quality-of-life-threatening disease.

Animals↗
PubMed2004

Developmental expression of receptor for advanced glycation end products (RAGE), amphoterin and sulfoglucuronyl (HNK-1) carbohydrate in mouse cerebellum and their role in neurite outgrowth and cell migration.

Receptor for advanced glycation end products (RAGE) has been proposed as a signal transduction receptor to promote neurite outgrowth and cell migration, by its interaction with a neurite outgrowth promoting protein, Amphoterin. Amphoterin has been shown to interact with sulfoglucuronyl carbohydrate (SGC). The developmental expression of RAGE, Amphoterin and SGC was studied in pre-natal and post-natal mouse cerebellum to establish their cellular and subcellular localization and function. The amount of RAGE in the cerebellum increased with age. RAGE was expressed pre-natally in the external germinal layer and post-natally in the plasma membranes of the granule neurons of the external and internal granule cell layers and in Purkinje cells. Immunocytochemical analysis by high magnification confocal microscopy showed that RAGE was co-expressed with Amphoterin and SGC in the cell surfaces of granule neurons. This co-localization of RAGE, Amphoterin, and SGC was confirmed in isolated and cultured granule neurons and in migrating granule neurons in explant cultures. Anti-RAGE antibodies inhibited neurite outgrowth and cell migration in explant and slice cultures, similar to anti-Amphoterin and anti-SGC antibodies shown previously. The results suggest that RAGE could act as a signaling molecule for neurite outgrowth and cell migration by its interaction with Amphoterin and that of Amphoterin with SGC.

Age Factors↗
PubMed1996

The receptor for advanced glycation end products (RAGE) is a central mediator of the interaction of AGE-beta2microglobulin with human mononuclear phagocytes via an oxidant-sensitive pathway. Implications for the pathogenesis of dialysis-related amyloidosis.

An important component of amyloid fibrils in dialysis-related amyloidosis is a form of beta2microglobulin modified with advanced glycation end products (AGEs) of the Maillard reaction, known as AGE-beta2M. We demonstrate here that the interaction of AGE-beta2M with mononuclear phagocytes (MPs), cells important in the pathogenesis of the inflammatory arthropathy of dialysis-related amyloidosis, is mediated by the receptor for AGEs, or RAGE. 125I-AGE-beta2M bound to immobilized RAGE or to MPs in a specific, dose-dependent manner (Kd approximately 53.5 and approximately 81.6 nM, respectively), a process inhibited in the presence of RAGE blockade. AGE-beta2M-mediated monocyte chemotaxis was prevented by excess sRAGE or anti-RAGE IgG. Induction of tumor necrosis factor-alpha (TNF) expression by MPs exposed to AGE-beta2M resulted from engagement of RAGE, as appearances of TNF transcripts and TNF antigen release into culture supernatants were prevented by addition of sRAGE, a process mediated, at least in part, by oxidant stress. AGE-beta2M reduced cytochrome c and the elaboration of TNF by MPs was inhibited by N-acetylcysteine. Consistent with these data, immunohistochemical studies of AGE-laden amyloid deposits of a long-term hemodialysis patient revealed positive staining for RAGE in the MPs infiltrating these lesions. These data indicate that RAGE is a central binding site for AGEs formed in vivo and suggest that AGE-beta2M-MP-RAGE interaction likely contributes to the initiation of an inflammatory response in amyloid deposits of long-term hemodialysis patients, a process which may ultimately lead to bone and joint destruction.

Amyloidosis↗
PubMed2003

Central role of RAGE-dependent neointimal expansion in arterial restenosis.

Cellular proliferation, migration, and expression of extracellular matrix proteins and MMPs contribute to neointimal formation upon vascular injury. Wild-type mice undergoing arterial endothelial denudation displayed striking upregulation of receptor for advanced glycation end products (RAGE) in the injured vessel, particularly in activated smooth muscle cells of the expanding neointima. In parallel, two of RAGE's signal transducing ligands, advanced glycation end products (AGEs) and S100/calgranulins, demonstrated increased deposition/expression in the injured vessel wall. Blockade of RAGE, employing soluble truncated receptor or antibodies, or in homozygous RAGE null mice, resulted in significantly decreased neointimal expansion after arterial injury and decreased smooth muscle cell proliferation, migration, and expression of extracellular matrix proteins. A critical role for smooth muscle cell RAGE signaling was demonstrated in mice bearing a transgene encoding a RAGE cytosolic tail-deletion mutant, specifically in smooth muscle cells, driven by the SM22alpha promoter. Upon arterial injury, neointimal expansion was strikingly suppressed compared with that observed in wild-type littermates. Taken together, these data highlight key roles for RAGE in modulating smooth muscle cell properties after injury and suggest that RAGE is a logical target for suppression of untoward neointimal expansion consequent to arterial injury.

Animals↗
PubMed2006

Activation of RAGE induces elevated O2- generation by mononuclear phagocytes in diabetes.

Oxidative stress has been found to play a role in the pathogenesis of diabetic complications. The aim of this study was to define the oxidative burst of diabetic monocytes to characterize the phenotype associated with poor diabetic control. Superoxide (O(2)(-)) is the first molecule generated during the respiratory burst of phagocytes by NADPH oxidase, and its generation by monocytes from 26 controls and 34 diabetic subjects was evaluated in this study. Under resting states or stimulation by PMA or opsonized zymosan, diabetic monocytes produce significantly more O(2)(-) than nondiabetic cells. The increased O(2)(-) generation was found to be correlated with glycemic control (glycated hemoglobin) of patients. To clarify the effects of hyperglycemia on O(2)(-) generation, normal human monocytes were treated with receptor for advanced glycation endproducts (RAGE) ligands (AGE protein and S100B) or high glucose media before stimulation. RAGE ligands and high glucose concentration increased O(2)(-) generation from human mononuclear phagocytes. RAGE ligands, specifically and potently, increased O(2)(-) generation from mononuclear phagocytes, and high-glucose effects were associated with correspondingly increased osmotic pressure. Differentiated THP-1 cells, from a human monocytic cell line, were used as a model of human monocytes to study the effects of S100B, the RAGE ligand. It was confirmed that RAGE is involved in the priming of O(2)(-) generation by S100B. This study demonstrates that RAGE ligands can contribute significantly to the hyper-responsive phenotype of diabetic monocytes, which might be reversible by blocking the RAGE or controlling the presence of RAGE ligands by controlling hyperglycemia.

Adult↗
PubMed2001

Characterization of allelic and nucleotide variation between the RAGE gene on chromosome 6 and a homologous pseudogene sequence to its 5' regulatory region on chromosome 3: implications for polymorphic studies in diabetes.

Activation of the receptor for advanced glycation end products (RAGE) appears to be a key mechanism in the pathogenesis of diabetic vascular disease, making RAGE a candidate gene for investigation. RAGE is located in the major histocompatibility complex locus on chromosome 6, which contains a multitude of overlapping and duplicated genes involved predominantly in inflammatory and immune responses. The RAGE 5' flanking region from -505 in a 5' direction overlaps with PBX2, a gene that has a pseudogene copy on chromosome 3, making any studies of polymorphisms in this duplicated region potentially fraught with error. In this study we have addressed these issues by confirming RAGE as a predominantly single-copy gene and PBX2 to have two gene copies in the haploid human genome. We have characterized the gene:pseudogene differences between RAGE/PBX2 on chromosome 6 and PsiPBX2 on chromosome 3, which include a change from C to A at position -1139 RAGE/+2298 PBX2, previously reported as a polymorphism. Single chromosome-specific DNA amplification of the duplicated region has clarified five polymorphisms to be on chromosome 3 and one (at -1202 RAGE/+2234 PBX2) to be on chromosome 6. In conclusion, this study provides essential data for the study of RAGE and its genetics.

3' Untranslated Regions↗
PubMedDate not supplied

Differential expression of RAGE in human pancreatic carcinoma cells.

BACKGROUND/AIMS: Amphoterin is a key protein in normal neurite outgrowth and that its receptor on the cell surface, RAGE, is an important molecule for invasion. RAGE induces neurite outgrowth and regulate gene expression through NF-kappa B. Because the pancreatic cancer shows the constitutively activated NF-kappa B, the involvement of RAGE could be possible as a determinant for the metastatic ability. METHODOLOGY: To see the involvement of RAGE in pancreatic cancer, three representative human pancreatic carcinoma cells were rendered for the study which have different metastatic potential, PANC-1 and MIA PaCa-2 as the cells with high ability, BxPC-3 as those with low. The expression of RAGE (receptor for advanced glycation end-products) was examined by Western blot. RESULTS: The expression of RAGe was strong in MIA PaCa-2 and PANC-1 that have high metastatic ability. On the contrary, RAGE is expressed little in BxPC-3 whose ability is low. CONCLUSIONS: RAGE is expressed in concordant to the metastatic ability of the human pancreatic cancer cells. Control of this molecule could be a key to regulate the metastatic ability of pancreatic cancer.

Blotting, Western↗
PubMedDate not supplied

The John F. Maher Recipient Lecture 2004: Rage in the peritoneum.

Several conditions in the peritoneal membrane of peritoneal dialysis (PD) patients promote the accumulation of advanced glycation end-products (AGEs), that is, the uremic state, exposure to high glucose concentrations, and exposure to glucose degradation products (GDPs). AGEs exert some of their biologic actions through binding with a cell surface receptor, termed RAGE. Interaction of AGEs with RAGE induces sustained cellular activation, including the production of the fibrogenic growth factor, transforming growth factor-beta (TGF-beta). TGF-beta is pivotal in the process of epithelial-to-mesenchymal transition, through which cells of epithelial origin acquire myofibroblastic characteristics. Myofibroblasts are involved in virtually all conditions of pathological fibrosis. Submesothelial fibrosis is an important feature in peritoneal biopsies of PD patients, especially of those with clinical problems. We therefore examined the role of RAGE in peritoneal fibrosis, in an animal model of uremia, of high glucose exposure, and of peritoneal dialysate exposure. All three models were characterized by accumulation of AGEs, upregulation of RAGE, and fibrosis. Antagonism of RAGE prevented the upregulation of TGF-beta and fibrosis in the peritoneal membrane. We further examined the underlying mechanism of peritoneal fibrosis in the uremic model. Prominent myofibroblast transdifferentiation of mesothelial cells was identified by co-localization of cytokeratin and alpha-smooth muscle actin in submesothelial and interstitial fibrotic tissue. Antagonism of RAGE prevented conversion of mesothelial cells to myofibroblasts in uremia. In conclusion, we hypothesize that accumulation of AGEs in the peritoneal membrane, as a consequence of the uremic environment, chronic exposure to high glucose, and exposure to GDPs, results in an increased expression of RAGE. The interaction of AGEs with RAGE induces peritoneal fibrosis by virtue of upregulation of TGF-beta and subsequent conversion of mesothelial cells into myofibroblasts.

Dialysis Solutions↗
PubMed1998

Receptor for advanced glycation endproducts (RAGE) exhibits highly differential cellular and subcellular localisation in rat and human lung.

The transmembrane receptor (RAGE) of advanced glycation endproducts (AGEs), is abundantly present in the lung. Although the interaction of AGEs and RAGE plays an important role in vasculopathies, particularly in diabetes, the lung is not a classical target organ of diabetes. Thus, the role of RAGE in the lung is still obscure. This study sought to precisely localise RAGE in the lungs of rat and human by immunohistochemistry, double immunofluorescence and immunoelectron microscopy using a polyclonal antiserum developed against human recombinant RAGE. Anti-RAGE immunoreactivity was prominent in alveolar epithelial type I pneumocytes, while it was absent from type II pneumocytes and capillary endothelium. Cell type specificity was demonstrated by colocalisation with well established cell markers. Quantitative immunoelectron microscopy of cryo-substituted, Lowicryl-embedded rat and human specimens demonstrated a unique labelling pattern of RAGE in that it selectively localised to the basal cell membrane of type I pneumocytes. Labelling pattern was independent of the mode of fixation. Equivalent labelling densities were calculated from a fibrotic rat lung 3 months after irradiation. This highly selective localisation of RAGE to the basal face of type I pneumocytes and its absence from capillary endothelium might explain the resistance of the lung to typical diabetic complications.

Animals↗
PubMed1992

Role of NMDA receptors in hypothalamic facilitation of feline defensive rage elicited from the midbrain periaqueductal gray.

The present study tested the hypothesis that the pathway from the medial hypothalamus to the midbrain periaqueductal gray (PAG) subserving defensive rage behavior in the cat facilitates the occurrence of this response when elicited from the PAG by utilizing excitatory amino acids as a neurotransmitter or neuromodulator. Cannula electrodes were implanted into the PAG for the elicitation of defensive rage behavior as well as for microinjections of excitatory amino acid antagonists and N-methyl-D-aspartic acid (NMDA). Monopolar stimulating electrodes were also implanted into the medial hypothalamus from which this response could also be elicited and, when stimulated at subthreshold levels for elicitation of behavior, could also facilitate the occurrence of PAG elicited defensive rage. Initially, dual stimulation of the PAG and medial hypothalamus facilitated the occurrence of defensive rage elicited from the PAG. Then, the identical dual stimulation paradigm was repeated with the same current parameters following the infusion of various antagonists for different receptors into the PAG defensive rage sites. The results indicate that infusion of either kynurenic acid [(0.1-2.0 nmol), a non-selective excitatory amino acid receptor antagonist] or D-2-amino-7-phosphonoheptanoic acid (AP7) [(0.1-2.0 nmol), a specific NMDA receptor antagonist], produced a dose and time dependent blockade of the facilitatory effects of medial hypothalamic stimulation. In contrast, microinjections of relatively larger doses of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) [(4 nmol), a non-NMDA receptor (quisqualate and kainate) antagonist] or atropine [(4.4 nmol), a muscarinic receptor antagonist] had little effect upon medial hypothalamically elicited facilitation of the PAG response. In a second experiment, NMDA [0.1-1.0 nmol] was microinjected directly into PAG defensive rage sites in the absence of medial hypothalamic stimulation. In these animals, drug infusion mimicked the effects of dual stimulation by producing a dose and time dependent decrease in response latencies. A third experiment was designed to further test the hypothesis by neuroanatomical methods. Here, the retrograde label, Fluoro-Gold, was microinjected into defensive rage sites within the PAG and following a survival time of 5-6 days, the animals were sacrificed. The brains were then processed for immunocytochemical analysis of cells that immunoreact positively for aspartate and glutamate. The results indicated the presence of many retrogradely labelled and immunocytochemically positive cells within the rostro-caudal extent of the medial hypothalamus as well as others that were double labelled.(ABSTRACT TRUNCATED AT 400 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed2003

Differential effects of NK1 receptors in the midbrain periaqueductal gray upon defensive rage and predatory attack in the cat.

This study utilized anatomical and behavioral-pharmacological methods to determine the role of NK(1)-Substance P receptors in the midbrain periaqueductal gray (PAG) in defensive rage behavior in cats. For behavioral pharmacological experiments, monopolar stimulating electrodes were implanted in the medial hypothalamus for elicitation of defensive rage behavior and cannula-electrodes were implanted in the PAG for microinjections of receptor compounds. Microinjections of the NMDA antagonist, AP-7 (2 nmol), into the dorsal PAG blocked defensive rage elicited by medial hypothalamic stimulation, thus establishing the PAG as a synaptic region that receives hypothalamic inputs linked to defensive rage behavior. Microinjections of the NK(1) agonist, GR73632, into the same injection sites facilitated defensive rage in a dose-dependent manner, and also induced spontaneous hissing in five cats. The effects of GR73632 were reduced by pretreatment of the PAG with the NK(1) antagonist, GR82334 (16 nmol), microinjected into the same sites. Microinjections of GR73632 (8 nmol) into the PAG also suppressed predatory attack elicited by stimulation of the lateral hypothalamus. Immunohistochemical methods utilized to detect Substance P and Fos immunoreactivity revealed that neurons in the PAG activated after defensive rage-inducing medial hypothalamic stimulation lie in the same region as Substance-P-immunoreactive processes. Fos immunoreactivity was highest in the dorsomedial aspect of the rostral PAG after medial hypothalamic stimulation. Cats that were unstimulated or that exhibited predatory attack after lateral hypothalamic stimulation had low c-fos expression levels in the PAG. Substance P immunoreactivity was high throughout the dorsal PAG. The results indicate that NK(1) receptors in the PAG potentiate defensive rage and suppress predatory aggression in the cat.

Animals↗
PubMed2005

Cytokine modulation of defensive rage behavior in the cat: role of GABAA and interleukin-2 receptors in the medial hypothalamus.

Defensive rage behavior is a form of aggressive behavior occurring in nature in response to a threatening stimulus. It is also elicited by stimulation of the medial hypothalamus and midbrain periaqueductal gray (PAG) and mediated through specific neurotransmitter-receptor mechanisms within these regions. Since interleukin (IL)-2 modulates the release of neurotransmitters linked to aggression and rage, we sought to determine whether IL-2 microinjected into the medial hypothalamus would modulate defensive rage. Microinjections of relatively low doses of IL-2 into the medial hypothalamus significantly suppressed defensive rage elicited from the PAG in a dose-dependent manner and in the absence of signs of sickness behavior. Pre-treatment with an antibody directed against IL-2Ralpha or a GABA(A) receptor antagonist blocked IL-2's suppressive effects upon defensive rage. Since the suppression of defensive rage is also mediated by 5-HT(1) receptors in the medial hypothalamus, a 5-HT(1) antagonist was microinjected into this region as a pretreatment for IL-2; however, it did not block IL-2's suppressive effects. Immunocytochemical data provided anatomical support for these findings by revealing extensive labeling of IL-2Ralpha on neurons in the medial hypothalamus. IL-2 microinjected into the medial hypothalamus did not modulate predatory attack elicited from the lateral hypothalamus. In summary, we provide evidence for a novel role for IL-2 in the medial hypothalamus as a potent suppressor of defensive rage behavior. These effects are mediated through an IL-2-GABA(A) receptor mechanism.

Aggression↗
PubMed2003

NK1 receptors in the medial hypothalamus potentiate defensive rage behavior elicited from the midbrain periaqueductal gray of the cat.

Defensive rage in the cat occurs naturally in response to a threat and is also elicited by electrical or chemical stimulation over the rostro-caudal extent of the medial hypothalamus and dorsolateral aspect of the periaqueductal gray (PAG). This behavior is mediated over a descending projection from the hypothalamus to the midbrain PAG. The underlying hypothesis for the present study was that medial hypothalamic defensive rage neurons are excited in two ways: by NK(1) receptors and by an ascending input from the PAG. The first aspect of this hypothesis was tested by eliciting defensive rage by electrical stimulation of the PAG and then microinjecting a selective NK(1) agonist and antagonist into the hypothalamus. Microinjections of 16 or 12 nmol/0.25 microl of the NK(1) agonist, GR 73632, resulted in facilitation of defensive rage. These facilitatory effects were then blocked by pretreatment with the NK(1) antagonist, GR 82334. However, microinjections of GR 82334 alone had no effect. The second aspect of the hypothesis was tested by stimulating defensive rage sites in the PAG and using immunohistochemical methods to test for the presence of c-Fos in the hypothalamus. The results revealed the presence of c-Fos immunoreactivity in the medial but not lateral hypothalamus. Overall, the findings indicate that NK(1) receptors in the medial hypothalamus facilitate defensive rage elicited from PAG neurons whose axons project back to the medial hypothalamus. The likely ethological significance of the ascending input is that it allows for potentiation and prolongation of defensive rage in response to a threatening stimulus.

Animals↗
PubMed2003

Differential modulation of feline defensive rage behavior in the medial hypothalamus by 5-HT1A and 5-HT2 receptors.

Previous studies have established that the expression of defensive rage behavior in the cat is mediated over reciprocal pathways that link the medial hypothalamus and the dorsolateral quadrant of the midbrain periaqueductal gray matter (PAG). The present study was designed to determine the roles played by 5-HT(1A) and 5-HT(2C) receptors in the medial hypothalamus on the expression of defensive rage behavior elicited from electrical stimulation of the PAG. Monopolar stimulating electrodes were placed in the midbrain PAG from which defensive rage behavior could be elicited by electrical stimulation. During the course of this study, defensive rage was determined by measuring the latency of the "hissing" component of this behavior. Cannula-electrodes were implanted into sites within the medial hypothalamus from which defensive rage behavior could also be elicited by electrical stimulation in order that serotonergic compounds could be microinjected into behaviorally identifiable regions of the hypothalamus at a later time. Microinjections of the 5-HT(1A) receptor agonist 8-OHDPAT (0.1, 1.0 and 3.0 nmol) into the medial hypothalamus suppressed PAG-elicited hissing in a dose-dependent manner. Administration of the 5-HT(1A) antagonist p-MPPI (3.0 nmol) blocked the suppressive effects of 8-OHDPAT upon hissing. The suppressive effects of 8-OHDPAT were specific to defensive rage behavior because this drug (3 nmol) facilitated quiet biting attack. Microinjections of the 5-HT(2C) receptor agonist (+/-)-DOI hydrochloride into the medial hypothalamus (0.5, 1.0, and 3.0 nmol) facilitated the occurrence of PAG-elicited hissing in a dose-dependent manner. In turn, these facilitating effects were blocked by pretreatment with the selective 5-HT(2) antagonist, LY-53,857, which was microinjected into the same medial hypothalamic site. The findings of this study provide evidence that activation of 5-HT(1A) and 5-HT(2) receptors within the medial hypothalamus exert differential modulatory effects upon defensive rage behavior elicited from the midbrain PAG of the cat.

8-Hydroxy-2-(di-n-propylamino)tetralin↗