Effects of the selective 5-HT1A receptor antagonist WAY100135 and its enantiomers on 8-OH-DPAT-induced hyperglycaemia in conscious rats

Critchley, David; Middlefell, Vicki C.; Liddle, Christopher; Foden, Nigel D.; Dourish, C T

doi:10.1016/0014-2999(94)90380-8

Cited by 17 publications

(11 citation statements)

References 33 publications

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“…It has been reported that 8-OH-DPAT induces hyperglycemia in rats and mice. 3,5,14) Our present results are consistent with previous reports. The present results demonstrate that 8-OH-DPAT increases plasma glucagon levels in rats.…”

Section: Discussionsupporting

confidence: 93%

“…3,5,7) Hyperglycemia induced by 8-OH-DPAT is accompanied by a decrease in blood insulin. Chaouloff et al reported that 8-OH-DPAT decreases the insulin release stimulated by glucose.…”

mentioning

confidence: 99%

“…[3][4][5][6] These responses are mediated by the post-synaptic 5-HT 1A receptor, since they were antagonized by 5-HT 1A receptor antagonists but not reduced by 5-HT depletion. 3,5,7) Hyperglycemia induced by 8-OH-DPAT is accompanied by a decrease in blood insulin. Chaouloff et al reported that 8-OH-DPAT decreases the insulin release stimulated by glucose.…”

mentioning

confidence: 99%

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The 5-HT1A Receptor Agonist 8-Hydroxy-2-di-n-(propylamino)tetralin (8-OH-DPAT) Induces Hyperglucagonemia in Rats.

Sugimoto

Kimura

Watanabe

et al. 2001

Biological & Pharmaceutical Bulletin

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The 5-HT 1A receptor relates to anxiety or depression and administration of 5-HT 1A receptor agonists displays anxiolytic and antidepressant effects in both humans and animals.1) It is suggested that the 5-HT 1A receptor is associated with endocrine function, thus regulating corticosterone or prolactin release.2) 8-Hydroxy-2-di-n-(propylamino)tetralin (8-OH-DPAT) is a full agonist at the 5-HT 1A receptor and extensively used for investigation of the 5-HT 1A receptor function. It has been suggested that 5-HT is involved in glucose regulation, since stimulation of the central 5-HT 1A receptor results in hyperglycemia in rats. The 5-HT 1A receptor full agonist 8-OH-DPAT and 5-HT 1A receptor partial agonists including buspirone and ipsapirone induce hyperglycemia in rats.3-6) These responses are mediated by the post-synaptic 5-HT 1A receptor, since they were antagonized by 5-HT 1A receptor antagonists but not reduced by 5-HT depletion. 3,5,7) Hyperglycemia induced by 8-OH-DPAT is accompanied by a decrease in blood insulin. Chaouloff et al. reported that 8-OH-DPAT decreases the insulin release stimulated by glucose.3) This is mediated by stimulation of a 2 adrenoceptors in the pancreatic islet following the enhancement of adrenaline release from the adrenal gland. 3,8) The pancreatic hormones insulin and glucagon regulate glucose homeostasis. It has been also suggested that the 5-HT 2 receptor participates in glucose regulation. 9) We previously found that the 5-HT 2A receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane (DOI) and the 5-HT 2C/2B receptor agonist mchlorophenylpiperazine (mCPP) induced hyperglycemia and increased plasma glucagon levels of rats.10-13) Although 8-OH-DPAT affects insulin secretion in vivo, little is known about whether it modifies circulating glucagon levels. This paper investigated the effects of the 5-HT 1A receptor agonist 8-OH-DPAT on glucagon secretion in rats and the involvement of glucagon in glycemic responses to 8-OH-DPAT. MATERIALS AND METHODSMale Sprague-Dawley rats (180-230 g) were purchased from SLC Japan, Inc. (Japan). Rats were maintained under a controlled 12 h/12 h light dark cycle (light from 7 : 00 a.m. to 7 : 00 p.m.), with a room temperature of 23Ϯ1°C and 55Ϯ5% humidity. All animals were given free access to food and water before the experiments. Blood samples were taken from the caudal vena cava under ether anesthesia. Only one sample was removed from each rat. Plasma glucose levels were determined by the method previously described. 6) Glucagon levels were measured by radioimmunoassay using the commercially available kit, Glucagon Daiichi (Daiichi Radioisotope Center, Japan).Bilateral adrenodemedullation was performed under anesthesia with pentobarbital Na at 50 mg/kg. Experiments were carried out one week after the operation. After the experiments, the adrenodemedullated rats were killed and it was verified that the adrenal medulla was removed and that the adrenal cortex was preserved.Statistical significance was evaluated by Student's t-test for comparison...

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Section: Discussionsupporting

confidence: 93%

“…3,5,7) Hyperglycemia induced by 8-OH-DPAT is accompanied by a decrease in blood insulin. Chaouloff et al reported that 8-OH-DPAT decreases the insulin release stimulated by glucose.…”

mentioning

confidence: 99%

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The 5-HT1A Receptor Agonist 8-Hydroxy-2-di-n-(propylamino)tetralin (8-OH-DPAT) Induces Hyperglucagonemia in Rats.

Sugimoto

Kimura

Watanabe

et al. 2001

Biological & Pharmaceutical Bulletin

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“…Only until very recently, no full 5-HT 1A receptor antagonists were available for these studies. The identification of (S)WAY 100135 and WAY 100635 as full 5-HT 1A receptor antagonists (Cliffe et al, 1993;Critchley et al, 1994;Fletcher et al, 1993a,b) prompted the intensive investigation of other potential full 5-HT 1A receptor antagonists. PET studies of [O-methyl-11 C]WAY 100635 in humans revealed that the distribution of radioactivity was highly localized and consistent with the known distribution of 5-HT 1A receptors .…”

Section: Resultsmentioning

confidence: 98%

“…BMY7378 appears to exhibit these same partial agonist properties (Greuel and Glaser, 1992). (S) WAY 100135, an arylpiperazine analog, appears to be a very highly selective and potent 5-HT 1A receptor antagonist at both the presynaptic (somatodendritic) and postsynaptic 5-HT 1A receptor sites (Cliffe et al, 1993;Critchley et al, 1994;Fletcher et al, 1993a,b). The IC 50 of (S) WAY 100135 is 15 nM in rat hippocampal membrane preparations.…”

Section: Introductionmentioning

confidence: 88%

p-[18F]-MPPF: A potential radioligand for PET studies of 5-HT1A receptors in humans

Shiue

Mozley

et al. 1997

Synapse

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The purpose of this study was to develop a radiopharmaceutical that could be used to selectively image 5-HT1A receptors with positron emission tomography (PET). No-carrier-added 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[18F] fluorobenzamido]ethylpiperazine (p-[18F]-MPPF, 2) was synthesized by the nucleophilic substitution of the corresponding nitro precursor 1 with K[18F]/Kryptofix 2.2.2. in dimethyl sulfoxide (DMSO) at 140 degrees C for 20 min followed by purification with high-performance liquid chromatography (HPLC) in 10% yield in a synthesis time of 90 min from end of bombardment (EOB). Specific activity was 1-4 Ci/microM. Biodistribution studies in rats showed that the initial uptake of 2 in the brain was high (0.7% dose/g tissue at 2 min). It was then rapidly eliminated. Rates of elimination were significantly slower in brain regions with high concentrations of 5-HT1A receptors (hippocampus, cortex, and hypothalamus) than in control regions. The maximum hippocampal/cerebellar ratio was 5.6:1 at 30 min postinjection. Uptake values in serotonergic, but not in control, regions were significantly reduced by prior treatment with either (+/-)-8-OH-DPAT (2 mg/kg, i.v., 5 min prior) or WAY 100635 (1 mg/kg, i.v., 5 min prior). Radioactivity in the femur did not increase with time, suggesting that in vivo defluorination may not be the major route of metabol sm. PET studies of 2 in a monkey demonstrated selective uptake and retention of 2 in the hippocampus. The hippocampal/cerebellar ratio was 3:1 at 30 min postinjection. The ratio was reduced to 1:1 by administering (+/-)-8-OH-DPAT (2 mg/kg, i.v.) 23 min postinjection of 2. Analyses of arterial plasma by HPLC revealed that 20% of radioactivity in the plasma remained as the parent compound 2 at 30 min postinjection. The results suggest that p-[18F]-MPPF may be a useful radioligand for studying cerebral 5-HT1A receptors in humans with PET techniques.

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The effect of urapidil and ramipril on hyperglycemia in streptozotocin diabetic rats

Ittner

Zimmermann

Bucher

et al. 2000

Naunyn-Schmiedeberg's Arch Pharmacol

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Angiotensin-converting enzyme inhibitors and alpha1-adrenoceptor antagonists improve glucose disposal in diabetes mellitus. We compared the effect of the antihypertensive hybrid drug urapidil [alpha1-adrenoceptor antagonist serotonin 1A (5-hydroxytryptamine 1A, 5-HT1A) receptor agonist] on hyperglycemia in streptozotocin diabetic rats with the angiotensin-converting enzyme inhibitor ramipril. 5-HT1A receptor agonists induce hyperglycemia. This could be an important disadvantage during treatment of diabetes mellitus with urapidil. Diabetes was induced by streptozotocin (70 mg/kg i.p.). Treatment for 7 days (ramipril 10 mg/kg p.o.; urapidil 20 mg/kg p.o.) significantly decreased mean blood glucose values (urapidil: 15.7+/-0.9 mmol/l, P=0.007; ramipril: 15.0+/-0.8 mmol/l, P=0.038 vs. diabetic control group: 18.7+/-1.0 mmol/l). Both drugs reduced significantly blood pressure, urinary glucose, water consumption, and food requirement. Serotonin concentration in the brain (medulla oblongata, pituitary) was not affected. A normalization comparable with healthy control rats was observed only in a diabetic control group with insulin therapy. In conclusion, our results demonstrate that the antihypertensive drug urapidil has no detrimental effect on hyperglycemia compared with the angiotensin-converting enzyme inhibitor ramipril in experimental diabetes mellitus despite its 5-HT1A receptor agonistic properties.

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Effects of the selective 5-HT1A receptor antagonist WAY100135 and its enantiomers on 8-OH-DPAT-induced hyperglycaemia in conscious rats

Cited by 17 publications

References 33 publications

The 5-HT1A Receptor Agonist 8-Hydroxy-2-di-n-(propylamino)tetralin (8-OH-DPAT) Induces Hyperglucagonemia in Rats.

The 5-HT1A Receptor Agonist 8-Hydroxy-2-di-n-(propylamino)tetralin (8-OH-DPAT) Induces Hyperglucagonemia in Rats.

p-[18F]-MPPF: A potential radioligand for PET studies of 5-HT1A receptors in humans

The effect of urapidil and ramipril on hyperglycemia in streptozotocin diabetic rats

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