Biomedical subjects

Koki Inoue

Publications and source records attributed to Koki Inoue.

14 recordsLinked to original sources

PubMed2006

Corticotropin-releasing factor receptor type 1, but not type 2, in the ventromedial hypothalamus modulates dopamine release in female rats.

Corticotropin-releasing factor (CRF) plays an important role in stress responses and is mediated through two subtypes of receptors, CRF receptor type 1 (CRFR1) and CRF receptor type 2 (CRFR2). Each CRF receptor might have a different function through several neurotransmitter systems; however, the mechanism remains unclear. To clarify the role of each receptor in dopamine (DA) metabolism, we measured the change of extracellular concentrations of DA and the metabolites in the ventromedial hypothalamus (VMH) that played important roles in the stress response of freely moving female rats in response to the direct administration of comparative CRFR1 selective agonist, CRF, or CRFR2 selective agonist, Urocortin II (Ucn II), into the brain region. Administration of 10 microg CRF increased extracellular concentrations of DA compared with 2 microg CRF immediately after injection, and this effect was not observed after 60 min of 10 microg CRF injection. On the other hand, this change did not always occur after Ucn II administration. These results suggest that the activation of CRFR1, but not CRFR2, modulates the release of DA in VMH.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2006

Delayed satiety-like actions and altered feeding microstructure by a selective type 2 corticotropin-releasing factor agonist in rats: intra-hypothalamic urocortin 3 administration reduces food intake by prolonging the post-meal interval.

Brain corticotropin-releasing factor/urocortin (CRF/Ucn) systems are hypothesized to control feeding, with central administration of 'type 2' urocortins producing delayed anorexia. The present study sought to identify the receptor subtype, brain site, and behavioral mode of action through which Ucn 3 reduces nocturnal food intake in rats. Non-food-deprived male Wistar rats (n=176) were administered Ucn 3 into the lateral (LV) or fourth ventricle, or into the ventromedial or paraventricular nuclei of the hypothalamus (VMN, PVN) or the medial amygdala (MeA), regions in which Ucn 3 is expressed in proximity to CRF(2) receptors. LV Ucn 3 suppressed ingestion during the third-fourth post-injection hours. LV Ucn 3 anorexia was reversed by cotreatment with astressin(2)-B, a selective CRF(2) antagonist and not observed following equimole subcutaneous or fourth ventricle administration. Bilateral intra-VMN and intra-PVN infusion, more potently than LV infusion, reduced the quantity (57-73%) and duration of ingestion (32-68%) during the third-fourth post-infusion hours. LV, intra-PVN and intra-VMN infusion of Ucn 3 slowed the eating rate and reduced intake by prolonging the post-meal interval. Intra-VMN Ucn 3 reduced feeding bout size, and intra-PVN Ucn 3 reduced the regularity of eating from pellet to pellet. Ucn 3 effects were behaviorally specific, because minimal effective anorectic Ucn 3 doses did not alter drinking rate or promote a conditioned taste aversion, and site-specific, because intra-MeA Ucn 3 produced a nibbling pattern of more, but smaller meals without altering total intake. The results implicate the VMN and PVN of the hypothalamus as sites for Ucn 3-CRF(2) control of food intake.

Amygdala↗

PubMed2006

Vaccination against weight gain.

Obesity endangers the lives of millions of people worldwide, through comorbidities such as heart disease, cancers, type 2 diabetes, stroke, arthritis, and major depression. New approaches to control body weight remain a high priority. Vaccines traditionally have been used to protect against infectious diseases and, more recently, for unconventional targets such as drug addiction. Methodologies that could specifically modulate the bioavailability of an endogenous molecule that regulates energy balance might provide a new foundation for treating obesity. Here we show that active vaccination of mature rats with ghrelin immunoconjugates decreases feed efficiency, relative adiposity, and body weight gain in relation to the immune response elicited against ghrelin in its active, acylated form. Three active vaccines based on the 28-aa residue sequence of ghrelin, a gastric endocrine hormone, were used to immunize adult male Wistar rats (n = 17). Synthetic ghrelin analogs were prepared that spanned residues 1-10 [ghrelin (1-10) Ser-3(butanoyl) hapten, Ghr1], 13-28 [ghrelin (13-28) hapten, Ghr2], and 1-28 [ghrelin(1-28) Ser-3(butanoyl) hapten, Ghr3], and included n-butanoyl esters at Ser-3. Groups immunized with Ghr1 or Ghr3 showed greater and more selective plasma binding capacity for the active, Ser-3-(n-octanoyl) form of ghrelin as compared with Ghr2 or keyhole limpet hemocyanin vaccinated controls. Accordingly, they gained less body weight, with sparing of lean mass and preferential reduction of body fat, consistent with reduced circulating leptin levels. The ratio of brain/serum ghrelin levels was lower in rats with strong anti-ghrelin immune responses. Effects were not attributable to nonspecific inflammatory responses. Vaccination against the endogenous hormone ghrelin can slow weight gain in rats by decreasing feed efficiency.

Amino Acid Sequence↗

PubMed2006

Epinephrine increases the extracellular lidocaine concentration in the brain: a possible mechanism for increased central nervous system toxicity.

BACKGROUND: Local anesthetics exert central nervous system (CNS) toxicity by inhibiting intracerebral neuronal activity, while epinephrine augments the CNS toxicity of intravenously administered local anesthetics. Viewed together, increases of extracellular concentrations of local anesthetics in the brain may be directly associated with increased CNS toxicity. The authors examined the hypothesis that epinephrine enhances the CNS toxicity of lidocaine by increasing the extracellular concentration in the brain. METHODS: An awake, spontaneously breathing rat model was used. Twenty male Sprague-Dawley rats received an intravenous infusion of lidocaine (3 mg x kg x min; group C) or lidocaine with epinephrine (3 mg x kg x min and 2 microg x kg x min, respectively; group E) for 10 min (n = 10 in each group). Effects of epinephrine on the convulsive dose and concentrations of total (protein-bound and unbound) and unbound lidocaine in plasma were examined. Concentrations of extracellular lidocaine in the cerebral nucleus accumbens were quantitatively determined by a microdialysis method. RESULTS: The convulsive dose of lidocaine was significantly lower in group E than in group C (22.4 +/- 5.5 vs. 27.9 +/- 3.1 mg/kg, respectively; P < 0.05). Overall concentrations and area under the plasma concentration-versus-time curve of unbound lidocaine in group E were significantly higher than those in group C. Concentrations of extracellular lidocaine in the nucleus accumbens in group E were comparable to those of unbound fraction in plasma and were also significantly higher than those in group C. CONCLUSIONS: Concomitant administration of epinephrine significantly enhanced the CNS toxicity of intravenously administered lidocaine. Increased extracellular concentration in the brain would be related to this mechanism.

Animals↗

PubMed2006

[Animal model of eating disorders].

Patients with eating disorders are increasing in number. Some neurocircuits concerned with feeding behavior might be dysfunctional in these patients with repeated expression of disorganized eating behavior like long-lasting dieting. These neuronal, or endocrinological dysfunctions might even be enhanced by psychological stress. To understand the biological bases of eating disorders is necessary to establish effective treatment. According to the clinical features of the patients, we have conducted some rat studies. We have found that space restriction stress enhances rebound hyperphagia induced by time-restricted scheduled feeding, and propose the phenomenon as a possible rat model of binge eating. We can speculate some part of the biological bases of human eating disorders, and effective prevention and treatment through such animal models.

Animals↗

PubMed2005

Measuring meals: structure of prandial food and water intake of rats.

Attempts to understand ingestion have sought to understand the control of meals. The present study evaluated a meal definition that included prandial drinking (drinking-explicit meals). The spontaneous nocturnal intake of male Wistar rats was studied. The meal breakpoint was defined as the interval between feeding or drinking events providing the most stable estimate of meal structure. Alternative breakpoints derived from prevailing methodology, log-survivorship, or frequency histogram analysis of interfeeding intervals without respect to drinking were compared (drinking-naive meals). Threshold interfeeding intervals that accounted for drinking indirectly were evaluated as surrogate breakpoints (drinking-implicit meals). Definitions were compared by determining which criterion better conformed to predictions of satiety. Microstructural differences resulting from the definitions were also studied. Under the drinking-explicit definition, rats averaged nine or ten 13-min meals/night, during which they consumed food and water equally in duration (5-6 min) and quantity (2.3 g). Individual differences were observed in microstructure measures. Meals defined by drinking-informed, but not drinking-naive, methods were followed by the behavioral satiety sequence and by an initially low likelihood of resuming feeding that monotonically increased with time. The drinking-explicit definition uniquely revealed preprandial and postprandial correlations of similar magnitude. Under drinking-informed definitions, food restriction increased meal size, whereas drinking-naive definitions increased meal frequency. Drinking-implicit definitions provided workable approximations of meal frequency and size but inferior estimates of feeding duration, eating rate, and the preprandial correlation. Thus log-survivorship analysis is not appropriate for identifying meal breakpoints, and the consideration of drinking in meal definitions can provide a better estimate of meal structure.

Algorithms↗

PubMed2005

Resistance to diet-induced obesity in mu-opioid receptor-deficient mice: evidence for a "thrifty gene".

Using pharmacological tools, a role for opioid receptors in the regulation of food intake has been documented. However, the involvement of specific receptor subtypes remains questionable, and little information is available regarding a role for opioid receptors in energy metabolism. Using adult male mice lacking the mu-opioid receptor (MOR) gene (MOR-/-), we show that the MOR is not essential for the maintenance of normal levels of ad libitum food intake but does modulate the efficiency of energy storage during high-fat diets through the regulation of energy partitioning. When fed a regular diet, MOR-/- mice displayed only subtle alterations in energy homeostasis, suggesting a relative overuse of fat as a fuel source in the fed state. When fed a high-fat diet, MOR-/- mice were resistant to obesity and impaired glucose tolerance, despite having similar energy intake to wild-type mice. This resistance to obesity was associated with a strong induction of the expression of key mitochondrial enzymes involved in fatty acid oxidation within skeletal muscle. This metabolic role of the MOR, which is consistent with the properties of a "thrifty gene," suggests that the MOR pathway is a potential target for pharmacological intervention in the treatment of obesity associated with the intake of fatty diets.

Animals↗

PubMed2004

Leptin and post-prandial satiety: acute central leptin more potently reduces meal frequency than meal size in the rat.

RATIONALE: Many attempts to understand ingestion have sought to clarify the control of meals. Little is known about the effects of the anorexogenic hormone leptin on meal patterning. OBJECTIVE: The present study sought to perform a dose-response analysis of the effects of acute central leptin administration on meal patterning using a validated, objective meal definition and to compare these results to those obtained with a previously used, subjective meal definition. METHODS: To validate the objective meal definition pharmacologically, the microstructural effects of the well-studied compound fenfluramine (SC 0, 1, 2, 4 mg/kg) on spontaneous nocturnal intake were determined in mature, non-deprived male Wistar rats (n=8) using a full Latin square design. The effects of intracerebroventricular leptin administration (0, 0.3, 1, 3, 6.25 microg; n=10) were also examined, and perceived meal patterns obtained from the objective and subjective definitions were compared. RESULTS: Fenfluramine reduced meal size and eating rate at doses that did not reduce meal frequency or duration. In contrast, comparably anorectic doses of leptin had potent post-meal satiety-like effects, reducing meal frequency and prolonging the intermeal interval without reducing average meal size, a finding opposite to that suggested by the previously used subjective meal definition. Unlike comparably and more anorectic doses of fenfluramine, leptin non-specifically reduced both prandial and non-prandial drinking. CONCLUSIONS: Acute increases in central leptin levels may potently augment post-prandial satiety and influence body-fluid homeostasis. The results reveal unappreciated central modes of action for the ob protein which qualitatively differ from the intra-meal satiating-like effects of fenfluramine.

Animals↗

PubMed2004

Reduction of anxiety after restricted feeding in the rat: implication for eating disorders.

BACKGROUND: Eating-disorder patients exhibit not only abnormal eating attitudes but also pathologic anxiety-like behaviors. The specific nature of the relationship between dieting and anxiety-like behavior is unknown. METHODS: To investigate the adaptational changes that resulted from chronic restricted scheduled feeding (2-hour access per day for 2 weeks) and subsequent free refeeding, longitudinal changes in the microstructure of feeding behavior were studied in male rats. To study the relationship between restricted feeding and anxiety-like behavior, separate rats were tested in the elevated plus-maze under the following conditions: 1) free feeding; 2) acute food restriction (2-hour access for 1 day); 3) chronic food restriction (for 10 days); or 4) postrecovery (after 10 days of free feeding subsequent to chronic food restriction). RESULTS: The effects of chronic food restriction on meal structure diminished within a few days after refeeding. Decreased anxiety-like behavior was seen during acute and chronic food restriction and did not reflect nonspecific behavioral activation. Anxiolytic-like effects persisted after 10 days of refeeding. CONCLUSIONS: Chronic food restriction produced reductions in anxiety-like behavior that persisted beyond the normalization of food intake patterns. The findings might have etiologic and pathophysiologic relevance for the restrained eating pattern in eating-disorder patients with comorbid anxious symptoms.

Adaptation, Psychological↗

PubMed2004

Human urocortin 2, a corticotropin-releasing factor (CRF)2 agonist, and ovine CRF, a CRF1 agonist, differentially alter feeding and motor activity.

Two corticotropin-releasing factor (CRF) receptor families have been identified (CRF1 and CRF2). Whereas anxiogenic-like roles for the CRF1 receptor have been identified, behavioral functions of the CRF2 receptor remain obscure. Urocortin 2 (Ucn 2), a CRF-related peptide that selectively binds CRF2 receptors, was recently identified and recognized for its central anorectic properties. The present study tested the hypothesis that the anorexigenic mode of action of Ucn 2 differed from that of ovine CRF (oCRF), a preferential CRF1 receptor agonist. The behavioral effects of intracerebroventricular administration of Ucn 2 were compared with those of oCRF in nondeprived male Wistar rats (n=102). Ucn 2 reduced 6-h food and water intake at doses that did not induce visceral illness (0.1, 1, and 10 microg), as indicated by kaolin intake. Ucn 2 retained its potent anorectic activity in rats receiving a highly palatable cafeteria diet, preferentially reducing intake of carbohydrate (CHO)-rich items while sparing intake of mixed-fat/CHO items. In contrast to Ucn 2, oCRF (10 microg) suppressed 6-h intake of cafeteria diet-fed rats without regard to macronutrient composition. Rather, oCRF most potently suppressed intake of preferred food items. Whereas oCRF had short-onset motor-activating effects, Ucn 2 had nondose-dependent, delayed-onset motor-suppressing effects. Thus, central infusion of a CRF2 receptor agonist suppressed intake of both bland and palatable diets without inducing behavioral arousal or malaise, and the profile of anorexigenic effects qualitatively differed from those of a CRF1 receptor agonist. The results suggest the existence of distinct forms of CRF1- and CRF2-mediated anorexia.

Animals↗

PubMed2004

Local perfusion of mCPP into ventromedial hypothalamic nucleus, but not into lateral hypothalamic area and frontal cortex, inhibits food intake in rats.

RATIONALE: The serotonergic (5-hydroxytryptamine, 5-HT) system is extensively implicated in feeding behavior. In recent years, 5-HT receptors have been classified into 14 subtypes, and activation of 5-HT1B and 5-HT2C receptors inhibits food intake in rats. However, the precise functions in local brain areas of these receptor subtypes are unclear. OBJECTIVES: Frontal cortex (FC), lateral hypothalamic area (LH), or ventromedial hypothalamic nucleus (VMH) are involved in control of feeding behavior. We investigated the effects of 5-HT1B and 5-HT2C receptor stimulations in the three local brain areas on feeding behavior and on 5-HT metabolism. METHODS: We perfused mCPP, 5-HT(1B/2C) agonist, at multiple doses via a microdialysis probe into the three local brain areas and observed food intake. Extracellular concentrations of 5-HT and 5-HIAA were measured simultaneously. RESULTS: Perfusion of 1 mM mCPP into VMH, but not into LH nor FC at any dose, induced significant reduction of food intake compared with control. The extracellular concentrations of 5-HT were markedly increased in all three areas, but the concentrations of 5-HIAA were not changed by mCPP perfusions. CONCLUSIONS: These results indicate that the effects of 5-HT1B or 5-HT2C receptor activation on feeding behaviors depended on the brain regions, and that 5-HT1B or 5-HT2C receptors in VMH, but not in FC or in LH, play important roles in the regulation of food intake. The results also suggested that mCPP acts not only as a 5-HT(1B/2C) agonist, but also as a 5-HT releaser or as a re-uptake inhibitor. Further studies using antagonists should be conducted.

Animals↗

PubMed2003

Human urocortin II, a selective agonist for the type 2 corticotropin-releasing factor receptor, decreases feeding and drinking in the rat.

Corticotropin-releasing factor (CRF) has been hypothesized to modulate consummatory behavior through the Type 2 CRF (CRF(2)) receptor. However, behavioral functions subserved by the CRF(2) receptor remain poorly understood. Recently, human urocortin II (hUcn II), a selective CRF(2) receptor agonist, was identified. To study the effects of this neuropeptide on ingestive behavior, we examined the effects of centrally infused hUcn II (i.c.v. 0, 0.01, 0.1, 1.0, 10.0 micro g) on the microstructure of nose-poke responding for food and water in nondeprived, male rats. Malaise-inducing properties of the peptide were monitored using conditioned taste aversion (CTA) testing. To identify potential sites of action, central induction of Fos protein expression was examined. hUcn II dose dependently reduced the quantity and duration of responding for food and water at doses lower (0.01-1.0 micro g) than that forming a CTA (10 micro g). Effects were most evident during hours 4 to 6 of the dark cycle. Meal pattern analysis showed that hUcn II potently (0.1 micro g) increased the satiating value of food. Rats ate and drank smaller and shorter meals without changing meal frequency. Rats also ate more slowly. hUcn II induced Fos in regions involved in visceral sensory processing and autonomic/neuroendocrine regulation and resembling those activated by appetite suppressants. hUcn II is a promising neuropeptide for investigating the role of the CRF(2) receptor in ingestive behavior.

Animals↗

PubMed2003

[Frégoli symptom].

Explore the source record for details and available documents.

Antidepressive Agents↗

PubMed2002

Human urocortin II: mild locomotor suppressive and delayed anxiolytic-like effects of a novel corticotropin-releasing factor related peptide.

Recently, human urocortin II (hUcn II), a member of the corticotropin-releasing factor (CRF) peptide family, was identified. The following experiments sought to compare the effects of this novel CRF-related peptide versus those of ovine CRF (oCRF) on locomotor activation and anxiety-related behavior, using the locomotor activity test and the elevated plus maze, respectively. To examine locomotor activity during the active (dark) and inactive (light) phases, rats were intracerebroventricularly (i.c.v.) injected with 0, 0.1, 1.0 or 10 microg of hUcn II (n=8/group active; n=6-9/group inactive) or oCRF (n=8/group active; n=8/group inactive) 2 h after the onset of their respective testing phase and monitored for 3 (inactive) or 5 (active) h. To compare the effects of CRF-related peptides on exploration of the elevated plus maze, rats were pretreated (i.c.v. 0, 0.1, 1.0 or 10 microg) with hUcn II (n=7-11/group) or oCRF (n=7-10/group), 10 min prior to testing. Delayed effects in the elevated plus maze were examined in rats injected with 1.0 microg of hUcn II (n=8/group) or oCRF (n=6-8/group), or vehicle (n=8/group) 1, 4 or 6 h before testing. In contrast to the activational effects of oCRF, hUcn II mildly suppressed locomotor activity during the inactive phase. hUcn II did not acutely affect open arm exploration in the elevated plus maze, whereas oCRF decreased this measure. However, hUcn II increased open arm exploration 4 h after injection. Thus, hUcn II exhibits mild motor suppressive effects and delayed anxiolytic-like effects, suggesting a time-dependent role for hUcn II in the regulation of stress-related behavior.

Animals↗