Inhibitory Effects of the 5-HT1A Receptor Agonist Buspirone on Stress-Induced Hyperglycemia in Mice: Involvement of Insulin and a Buspirone Metabolite, 1-(2-Pyrimidinyl)piperazine (1-PP)

Abstract

Benzodiazepine derivatives are widely used for anxiety, by the facilitation of GABA neurotransmission. It is well known that serotonin (5-HT) is involved in several neurological functions.1) The 5-HT 1A receptor is related to emotion and the 5-HT 1A receptor agonists induce anxiolytic and antidepressant effects in humans and animals. 2,3) Buspirone is known to be a 5-HT 1A receptor agonist and is used to treat anxiety.2) Stress induces several neuroendocrinological effects such as activation of the hypothalamus-pituitary-adrenal (HPA) axis and elicits activation of sympathetic tone. 4,5) Hyperglycemic responses to stress are recognized as an index of the sympathetic nervous system. 4) Stress induces changes in emotion and mood. 5) Recently, it was reported that the 5-HT 1A receptor agonist might be effective for stress-induced behavioral depressant symptoms. 2)Previous reports demonstrated that 5-HT receptor is involved in glucose regulation. The 5-HT 1A receptor agonist 8-OH-DPAT elicits hyperglycemia in rats and mice.6,7) The 5-HT 1A receptor partial agonist buspirone and ipsapirone elevate the glucose levels of rats. 8,9) These effects of 5-HT 1A receptor agonists are considered due to facilitating adrenaline release from the adrenal medulla.10,11) However, there may be species differences in the effects of buspirone on glucose levels between rats and mice. We previously reported that buspirone did not elevate glucose levels of mice and it increases serum insulin levels.12) In addition, buspirone reduces glucose-induced hyperglycemia in mice by increasing insulin levels. 12)It is well known that stress elicits hyperglycemia and stress-induced hyperglycemia may be a factor in contributing to diabetes. 4,13) Since buspirone is available in stressed-patients with accompanying with anxiety, the possibility that buspirone may also suppress stress-induced hyperglycemia is postulated. However, it is not clear whether buspirone modifies stress-elevated hyperglycemia. In this paper, we examined the effects of buspirone on stress-induced hyperglycemia and involvement of insulin in the effects of buspirone. MATERIALS AND METHODS AnimalsMale ddY mice weighing 28-32 g were obtained from SLC Japan Inc (Japan). Mice were fed with free access to food and water and they were housed under a controlled 12-h/12-h light-dark cycle (light from 7:00 a.m. to 7:00 p.m.), with room temperature at 23Ϯ1°C and humidity at 55Ϯ5%. For experiments with glucose, mice were fasted for 20 h. The experimental procedure was approved by the Kobe Pharmaceutical University Animal Care and Use Committee.Drug Treatment Buspirone HCl, 1-(2-pyrimidinyl)-piperazine (1-PP) HCl were obtained from Sigma (U.S.A.). Drugs were dissolved in saline. Buspirone and 1-PP were injected s.c. 30 min before immobilization stress.Immobilization and Determination of Plasma Glucose and Insulin Levels Mice were restrained by placing in individual wire cages (3.5 cmϫ8.3 cmϫ2.3 cm). After immobilization for 15, 30, 60 and 120 min, mice were immediately decapitated and blood ...

Evaluation of Subchronic Inhalation Toxicity of Dimethyl Disulfide in Rats

“…The increase of serum glucose level observed in the male 125-ppm group is believed to be consistent with mild stress, as it was associated with a significant increase in the relative weight of adrenal glands. It should be noted that the weights of adrenal and thymus glands and the serum glucose level are good biomarkers for determining the chronic stress response in humans and rodents (Marquez et al, 2004;Sugimoto et al, 2005). The decreased absolute liver weight and the increased relative kidney weight observed in the male 125-ppm group were not considered to be treatment related.…”

Evaluation of Buspirone on Streptozotocin Induced Type 1 Diabetes and Its Associated Complications

“…Various studies have been carried out to evaluate the effect of buspirone on glycemic status. Sugimoto et al reported that buspirone (10 mg/kg) reduced immobilization stress, induced hyperglycemia, and raised serum insulin levels of nonstressed and stressed mice [5]. They also reported that 1-PP, the major metabolite of buspirone inhibited stress, induced hyperglycemia and increased serum insulin levels of stressed mice [5].…”

“…Sugimoto et al reported that buspirone (10 mg/kg) reduced immobilization stress, induced hyperglycemia, and raised serum insulin levels of nonstressed and stressed mice [5]. They also reported that 1-PP, the major metabolite of buspirone inhibited stress, induced hyperglycemia and increased serum insulin levels of stressed mice [5]. In a clinical study, Ojha et al [6] reported that buspirone (10 mg/kg, p.o.)…”

An anxiolytic drug buspirone ameliorates hyperglycemia and endothelial dysfunction in type 2 diabetic rat model

“…Insulin levels decreased, blood glucose levels improved, and HOMA-IR index values decreased in our treatment groups, although the values in the BUS 5 and combined treatment groups were lower than in the other groups. There are a number of studies evaluating the effect of buspirone on glycemic status in the literature [26,27]. Buspirone decreased blood glucose levels in all studies, although its effects on insulin levels varied.…”