Multiple Serotonin Receptors: Opportunities for New Treatments for Obesity?

Dourish, C T

doi:10.1002/j.1550-8528.1995.tb00212.x

Cited by 95 publications

(51 citation statements)

References 84 publications

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“…[8][9][10] We previously reported that the peripheral 5-HT 2 receptor agonist a-methyl-5-HT, reduces food intake in fasted rats and that it is mediated by the peripheral 5-HT 2A receptor. 11) We also found that the peripheral 5-HT 3 receptor agonist 2-methyl-5-hydroxytryptamine did not affect food intake in rats, which implying that the peripheral 5-HT 3 receptor is not associated with food intake. 11) It is known that 2-deoxy-D-glucose(2-DG) prevents utilization of intracellular glucose and elicits neuroglucopenia, leading to hyperphagia.…”

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confidence: 62%

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Effects of Peripheral Administration of 5-Hydroxytryptamine (5-HT) on 2-Deoxy-D-glucose-Induced Hyperphagia in Rats.

Sugimoto

Yoshikawa

Yamada

2002

Biological & Pharmaceutical Bulletin

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Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter and regulates several physiological functions. It is well established that 5-HT is an important factor controlling food intake and that 5-HT depresses food intake in animals and humans mediated by 5-HT receptors.1-3) Activation of central 5-HT 1B , 5-HT 2A and 5-HT 2C receptors induces anorexia in rodents based on numerous results using 5-HT receptor agonists and antagonists.1,2,4-7) Direct administration of 5-HT into the brain also induces hypophagia in rodents and its effects may be elicited by these 5-HT receptors. 3)Peripherally administered 5-HT induces anorexia and this effect may be associated with peripheral 5-HT 2 receptors, since it was antagonized by the peripheral 5-HT 2 receptor antagonist xylamidine. [8][9][10] We previously reported that the peripheral 5-HT 2 receptor agonist a-methyl-5-HT, reduces food intake in fasted rats and that it is mediated by the peripheral 5-HT 2A receptor.11) We also found that the peripheral 5-HT 3 receptor agonist 2-methyl-5-hydroxytryptamine did not affect food intake in rats, which implying that the peripheral 5-HT 3 receptor is not associated with food intake. 11)It is known that 2-deoxy-D-glucose(2-DG) prevents utilization of intracellular glucose and elicits neuroglucopenia, leading to hyperphagia. 12,13) To date, 2-DG-induced feeding serves as an animal model of hyperphagia. However, the effects of 5-HT itself on 2-DG-induced hyperphagia remain unclear. In the present study, therefore, we investigated the effects of peripheral administration of 5-HT on hyperphagia elicited by 2-DG in rats.Since 2-DG induces glucoprivation by inhibition of glucose utilization of cells, it elevates plasma glucose levels to compensate it. 12,13) 2-DG-induced hyperphagia is elicited in response to low glucose levels in the brain. It suggests that facilitation of hyperglycemia may improve shortage of glucose in the brain by increasing glucose uptake to cells, which may lead to inhibition of hyperphagia. The peripheral 5-HT receptor participates in glucose regulation. [14][15][16][17] We reported that peripheral 5-HT elicits hyperglycemia in rats.16) Thus, 5-HT may affect food intake in 2-DG-treated rats through modifying glucose levels. We also examined effects of 5-HT on blood glucose levels in 2-DG-treated rats. MATERIALS AND METHODS AnimalsMale Sprague-Dawley rats (200-240 g) were obtained from SLC Japan. They were housed in individual cages and maintained under a controlled 12 h : 12 h light/dark cycle ( lights on at 07:00 h), with room temperature at 23Ϯ 1°C and humidity at 55Ϯ5% for at least 7 d prior to experiments. Rats were given free access to food and water.Drugs and Treatment 2-DG and 5-HT creatinine sulfate were purchased from Wako Pure Chemical Co. (Japan), Merck (Germany), respectively. Ketanserin tartrate were obtained from Research Biochemicals Inc. (U.S.A.). 2-DG, 5-HT and ketanserin were dissolved in saline. All drugs were injected i.p. 2-DG and 5-HT were injected i.p. simultaneously at opposite sites. Ket...

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confidence: 62%

“…2,3) In the peripheral system, 5-HT may be related to the regulation of food intake, since peripherally administered 5-HT, which did not cross the blood brain barrier, elicits anorexia in rats. [8][9][10] It is known that a glucose analog, 2-DG inhibits glucose utilization in the brain, leading to a marked hyperphagia in animals.…”

Section: Discussionmentioning

confidence: 99%

Effects of Peripheral Administration of 5-Hydroxytryptamine (5-HT) on 2-Deoxy-D-glucose-Induced Hyperphagia in Rats.

Sugimoto

Yoshikawa

Yamada

2002

Biological & Pharmaceutical Bulletin

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“…This phenomenon is age-dependent, beginning in "middle aged" mice. In addition, 5-HT 2C antagonists cause increased eating and weight gain (see Dourish, 1995). In this regard, low affinity of quetiapine for 5-HT 2C receptors may decrease its propensity for treatment-emergent weight gain.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Pharmacology of FMPD [6-Fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene]: A Potential Novel Antipsychotic with Lower Histamine H₁Receptor Affinity Than Olanzapine

Rasmussen

Benvenga²,

Bymaster³

et al. 2005

J Pharmacol Exp Ther

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FMPD [6-fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene] is a potential novel antipsychotic with high affinity for dopamine D 2 (K i ϭ 6.3 nM), 5-HT 2A (K i ϭ 7.3 nM), and 5-HT 6 (K i ϭ 8.0 nM) human recombinant receptors and lower affinity for histamine H 1 (K i ϭ 30 nM) and 5-HT 2C (K i ϭ 102 nM) human recombinant receptors than olanzapine. Oral administration of FMPD increased rat nucleus accumbens 3,4-dihyroxyphenylacetic acid concentrations (ED 200 ϭ 6 mg/kg), blocked 5-HT 2A agonist-induced increases in rat serum corticosterone levels (ED 50 ϭ 1.8 mg/kg), and inhibited the ex vivo binding of [ 125 I]SB-258585 [4-iodo-N-[4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-benzenesulfonamide] to striatal 5-HT 6 receptors (ED 50 ϭ 10 mg/kg) but failed to inhibit ex vivo binding of [ 3 H]pyrilamine to hypothalamic histamine H 1 receptors at doses of up to 30 mg/kg. In electrophysiology studies, acute administration of FMPD selectively elevated the number of spontaneously active A10 (versus A9) dopamine neurons and chronic administration selectively decreased the number of spontaneously active A10 (versus A9) dopamine neurons. FMPD did not produce catalepsy at doses lower than 25 mg/kg p.o. In Fos-induction studies, FMPD had an atypical antipsychotic profile in the striatum and nucleus accumbens and increased Fos expression in orexin-containing neurons of the hypothalamus. FMPD produced only a transient elevation of prolactin levels. These data indicate that FMPD is an orally available potent antagonist of dopamine D 2 , 5-HT 2A , and 5-HT 6 receptors and a weak antagonist of H 1 and 5-HT 2C receptors. FMPD has the potential to have efficacy in treating schizophrenia and bipolar mania with a low risk of treatmentemergent extrapyramidal symptoms, prolactin elevation, and weight gain. Clinical trials are needed to test these hypotheses.Olanzapine is effective in treating schizophrenia and bipolar mania (Beasley et al., 1996;Tohen et al., 2000). It is classified as an atypical antipsychotic in that it has therapeutic effects on the positive, negative, and cognitive symptoms of schizophrenia while having a low propensity to produce extrapyramidal symptoms (EPS) and prolactin elevation. However, many patients have observed weight gain associated with the treatment of olanzapine and other atypical antipsychotics (Wirshing, 2001).It has been hypothesized that blockade of the histamine H 1 receptor plays a critical role in antipsychotic treatmentemergent weight gain. Histamine has long been associated with the control of food intake. Histamine activates postsynaptic H 1 receptors in the ventromedial and para-ventricular nucleus of the hypothalamus to suppress feeding (Sakata et al., 1988;Ookuma et al., 1989), and H 1 knock-out mice develop diet-induced and age-related obesity (Masaki et al., 2001). In addition, a significant correlation between affinity for the human H 1 receptor and weight gain has been reported for antipsychotics (Kroeze et al., 2003). Thus, an a...

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“…These results suggest that compounds which indiscriminantly increase the availability of 5-HT at all 5-HT receptors (SSRI's and 5-HT releasers) will have complex effects on erection and sexual function. Furthermore, selective 5-HT 1a and 5-HT 1b agonists developed for treatment of disorders such as obesity, 24 migraine 25 and anxiety 26 may have an impact on erectile function in humans.…”

Section: Discussionmentioning

confidence: 99%

The effects of 5HT1 agonists on erection in rats in vivo and rabbit corpus cavernosum in vitro

Hayes

Adaikan

2002

Int J Impot Res

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Multiple Serotonin Receptors: Opportunities for New Treatments for Obesity?

Cited by 95 publications

References 84 publications

Effects of Peripheral Administration of 5-Hydroxytryptamine (5-HT) on 2-Deoxy-D-glucose-Induced Hyperphagia in Rats.

Effects of Peripheral Administration of 5-Hydroxytryptamine (5-HT) on 2-Deoxy-D-glucose-Induced Hyperphagia in Rats.

Preclinical Pharmacology of FMPD [6-Fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene]: A Potential Novel Antipsychotic with Lower Histamine H₁Receptor Affinity Than Olanzapine

The effects of 5HT1 agonists on erection in rats in vivo and rabbit corpus cavernosum in vitro

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Multiple Serotonin Receptors: Opportunities for New Treatments for Obesity?

Cited by 95 publications

References 84 publications

Effects of Peripheral Administration of 5-Hydroxytryptamine (5-HT) on 2-Deoxy-D-glucose-Induced Hyperphagia in Rats.

Effects of Peripheral Administration of 5-Hydroxytryptamine (5-HT) on 2-Deoxy-D-glucose-Induced Hyperphagia in Rats.

Preclinical Pharmacology of FMPD [6-Fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene]: A Potential Novel Antipsychotic with Lower Histamine H1Receptor Affinity Than Olanzapine

The effects of 5HT1 agonists on erection in rats in vivo and rabbit corpus cavernosum in vitro

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Preclinical Pharmacology of FMPD [6-Fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene]: A Potential Novel Antipsychotic with Lower Histamine H₁Receptor Affinity Than Olanzapine