Biol. Pharm. Bull. 38, 884–888 (2015)
884
Vol. 38, No. 6
Regular Article
Effects of the 5-HT1A Receptor Agonist Tandospirone on ACTH-Induced Sleep Disturbance in Rats Ryuki Tsutsui,a Kazuaki Shinomiya,b Toshiaki Sendo,a Yoshihisa Kitamura,*,a and Chiaki Kameic a
Department of Clinical Pharmacy, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University; 2–5–1 Shikata-cho, Kita-ku, Okayama 700–8558, Japan: b Department of Clinical Psycho-Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University; 1–1–1 Tsushima-naka, Kita-ku, Okayama 700–8530, Japan: and c Department of Pharmacology, Faculty of Pharmaceutical Sciences, Yasuda Women’s University; 6–13–1 Yasuhigashi, Asaminami-ku, Hiroshima 731–0513, Japan. Received December 25, 2014; accepted March 31, 2015 The aim of this study was to compare the effect of the serotonin (5-HT)1A receptor agonist tandospirone versus that of the benzodiazepine hypnotic flunitrazepam in a rat model of long-term adrenocorticotropic hormone (ACTH)-induced sleep disturbance. Rats implanted with electrodes for recording electroencephalogram and electromyogram were injected with ACTH once daily at a dose of 100 µg/rat. Administration of ACTH for 10 d caused a significant increase in sleep latency, decrease in non-rapid eye movement (non-REM) sleep time, and increase in wake time. Tandospirone caused a significant decrease in sleep latency and increase in non-REM sleep time in rats treated with ACTH. The effect of tandospirone on sleep patterns was antagonized by the 5-HT1A receptor antagonist WAY-100635. In contrast, flunitrazepam had no significant effect on sleep parameters in ACTH-treated rats. These results clearly indicate that long-term administration of ACTH causes sleep disturbance, and stimulating the 5-HT1A receptor by tandospirone may be efficacious for improving sleep in cases in which benzodiazepine hypnotics are ineffective. Key words tyric acid
sleep disturbance; adrenocorticotropic hormone; serotonin (5-HT)1A receptor; gamma-aminobu-
Eighty to ninety percent of patients with major depression have disturbed sleep patterns,1) and it is widely accepted that sleep disturbance may be a risk factor for and/or a prodromal symptom of depression.2–4) Furthermore, disturbed sleep is characteristic of individuals undergoing treatment for depression, as well as those exhibiting a relapse of depressive symptoms.3) Therefore the treatment of sleep disturbance is likely important in preventing the development of depression. Benzodiazepines and their analogues are commonly effective in the clinical treatment of sleep disturbances via their effects on the gamma-aminobutyric acid (GABA)-ergic system. The GABAergic system plays an important role in the control of the sleep–wake cycle; however, sensitivity to benzodiazepines has been shown decreased in depressed patients with disturbed sleep.5) Therefore it is conceivable that sleep patterns in these individuals are influenced by non-GABAergic systems. For example, abnormal functioning of the serotonergic system was proposed to be closely associated with depression and sleep disturbances.6,7) Furthermore, serotonin (5-HT)1A receptor agonists have been reported efficacious against depression; however, only a limited number of studies have supported the efficacy of 5-HT1A receptor agonists for improving sleep disturbance in depression in humans and animals.8) The hypothalamic-pituitary-adrenocortical (HPA) axis, which is activated in response to stress, may be hyperfunctional in patients with depression.9) Kitamura et al.10) reported an overactive HPA axis in rats chronically administered adrenocorticotropic hormone (ACTH) and indicated that this model may be useful for studying depression and tricyclic antidepressant treatment-resistant conditions. Although these rats have been demonstrated valuable as tricyclic antidepressant
treatment-resistant animals in the forced swim test, whether they are also useful as a model of sleep disturbance has not yet been investigated. In the present study, we looked at sleep parameters in rats administered ACTH. We also compared the effect of the 5-HT1A receptor agonist tandospirone with that of the benzodiazepine hypnotic flunitrazepam on sleep patterns.
MATERIALS AND METHODS Animals Male Wistar rats weighing 240–260 g (Japan SLC, Shizuoka, Japan) were maintained in an air-conditioned room with controlled temperature (24±2°C) and humidity (55±15%) under a light–dark cycle (lights on from 07 : 00 to 19:00). The rats were housed in plastic cages with sawdust and allowed free access to food and water. All procedures involving these animals were conducted in accordance with the Guidelines for Animal Experiments at Okayama University Advanced Science Research Center. Surgery Rats were anesthetized with pentobarbital sodium (Nembutal, 35 mg/kg intraperitoneally (i.p.); Abbott Laboratories, North Chicago, IL, U.S.A.) and fixed to a stereotaxic apparatus (SR-5N; Narishige, Tokyo, Japan). To record electroencephalogram (EEG), a stainless steel screw electrode (diameter, 0.5 mm; depth, 1.7 mm) was chronically implanted into the cortex (A, −4.5; L, +2.5), according to coordinates from the atlas of Paxinos and Watson.11) A stainless steel screw fixed in the left frontal bone served as a reference electrode. To record electromyogram (EMG), stainless steel wire electrodes (0.2 mm) were implanted into the dorsal neck muscle. These electrodes were connected to a miniature receptacle, and the entire assembly was fixed to the skull with
* To whom correspondence should be addressed. e-mail: [email protected] © 2015 The Pharmaceutical Society of Japan
Biol. Pharm. Bull. Vol. 38, No. 6 (2015)885
Fig. 2. Effect of Orally Administered Tandospirone on Sleep Parameters in ACTH-Treated Rats
Fig. 1.
Variations in Sleep–Wake Cycles in ACTH-Treated Rats
Sleep latency (A), non-REM sleep time (B), wake time (C), and REM sleep time (D) were measured in rats before (open column) and 1 d (light gray column), 5 d (dark gray column), and 10 d (filled column) after administration of ACTH. Columns and vertical bars represent mean±S.E.M. (n=8). **Significantly different versus before administration of ACTH (p
884
Vol. 38, No. 6
Regular Article
Effects of the 5-HT1A Receptor Agonist Tandospirone on ACTH-Induced Sleep Disturbance in Rats Ryuki Tsutsui,a Kazuaki Shinomiya,b Toshiaki Sendo,a Yoshihisa Kitamura,*,a and Chiaki Kameic a
Department of Clinical Pharmacy, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University; 2–5–1 Shikata-cho, Kita-ku, Okayama 700–8558, Japan: b Department of Clinical Psycho-Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University; 1–1–1 Tsushima-naka, Kita-ku, Okayama 700–8530, Japan: and c Department of Pharmacology, Faculty of Pharmaceutical Sciences, Yasuda Women’s University; 6–13–1 Yasuhigashi, Asaminami-ku, Hiroshima 731–0513, Japan. Received December 25, 2014; accepted March 31, 2015 The aim of this study was to compare the effect of the serotonin (5-HT)1A receptor agonist tandospirone versus that of the benzodiazepine hypnotic flunitrazepam in a rat model of long-term adrenocorticotropic hormone (ACTH)-induced sleep disturbance. Rats implanted with electrodes for recording electroencephalogram and electromyogram were injected with ACTH once daily at a dose of 100 µg/rat. Administration of ACTH for 10 d caused a significant increase in sleep latency, decrease in non-rapid eye movement (non-REM) sleep time, and increase in wake time. Tandospirone caused a significant decrease in sleep latency and increase in non-REM sleep time in rats treated with ACTH. The effect of tandospirone on sleep patterns was antagonized by the 5-HT1A receptor antagonist WAY-100635. In contrast, flunitrazepam had no significant effect on sleep parameters in ACTH-treated rats. These results clearly indicate that long-term administration of ACTH causes sleep disturbance, and stimulating the 5-HT1A receptor by tandospirone may be efficacious for improving sleep in cases in which benzodiazepine hypnotics are ineffective. Key words tyric acid
sleep disturbance; adrenocorticotropic hormone; serotonin (5-HT)1A receptor; gamma-aminobu-
Eighty to ninety percent of patients with major depression have disturbed sleep patterns,1) and it is widely accepted that sleep disturbance may be a risk factor for and/or a prodromal symptom of depression.2–4) Furthermore, disturbed sleep is characteristic of individuals undergoing treatment for depression, as well as those exhibiting a relapse of depressive symptoms.3) Therefore the treatment of sleep disturbance is likely important in preventing the development of depression. Benzodiazepines and their analogues are commonly effective in the clinical treatment of sleep disturbances via their effects on the gamma-aminobutyric acid (GABA)-ergic system. The GABAergic system plays an important role in the control of the sleep–wake cycle; however, sensitivity to benzodiazepines has been shown decreased in depressed patients with disturbed sleep.5) Therefore it is conceivable that sleep patterns in these individuals are influenced by non-GABAergic systems. For example, abnormal functioning of the serotonergic system was proposed to be closely associated with depression and sleep disturbances.6,7) Furthermore, serotonin (5-HT)1A receptor agonists have been reported efficacious against depression; however, only a limited number of studies have supported the efficacy of 5-HT1A receptor agonists for improving sleep disturbance in depression in humans and animals.8) The hypothalamic-pituitary-adrenocortical (HPA) axis, which is activated in response to stress, may be hyperfunctional in patients with depression.9) Kitamura et al.10) reported an overactive HPA axis in rats chronically administered adrenocorticotropic hormone (ACTH) and indicated that this model may be useful for studying depression and tricyclic antidepressant treatment-resistant conditions. Although these rats have been demonstrated valuable as tricyclic antidepressant
treatment-resistant animals in the forced swim test, whether they are also useful as a model of sleep disturbance has not yet been investigated. In the present study, we looked at sleep parameters in rats administered ACTH. We also compared the effect of the 5-HT1A receptor agonist tandospirone with that of the benzodiazepine hypnotic flunitrazepam on sleep patterns.
MATERIALS AND METHODS Animals Male Wistar rats weighing 240–260 g (Japan SLC, Shizuoka, Japan) were maintained in an air-conditioned room with controlled temperature (24±2°C) and humidity (55±15%) under a light–dark cycle (lights on from 07 : 00 to 19:00). The rats were housed in plastic cages with sawdust and allowed free access to food and water. All procedures involving these animals were conducted in accordance with the Guidelines for Animal Experiments at Okayama University Advanced Science Research Center. Surgery Rats were anesthetized with pentobarbital sodium (Nembutal, 35 mg/kg intraperitoneally (i.p.); Abbott Laboratories, North Chicago, IL, U.S.A.) and fixed to a stereotaxic apparatus (SR-5N; Narishige, Tokyo, Japan). To record electroencephalogram (EEG), a stainless steel screw electrode (diameter, 0.5 mm; depth, 1.7 mm) was chronically implanted into the cortex (A, −4.5; L, +2.5), according to coordinates from the atlas of Paxinos and Watson.11) A stainless steel screw fixed in the left frontal bone served as a reference electrode. To record electromyogram (EMG), stainless steel wire electrodes (0.2 mm) were implanted into the dorsal neck muscle. These electrodes were connected to a miniature receptacle, and the entire assembly was fixed to the skull with
* To whom correspondence should be addressed. e-mail: [email protected] © 2015 The Pharmaceutical Society of Japan
Biol. Pharm. Bull. Vol. 38, No. 6 (2015)885
Fig. 2. Effect of Orally Administered Tandospirone on Sleep Parameters in ACTH-Treated Rats
Fig. 1.
Variations in Sleep–Wake Cycles in ACTH-Treated Rats
Sleep latency (A), non-REM sleep time (B), wake time (C), and REM sleep time (D) were measured in rats before (open column) and 1 d (light gray column), 5 d (dark gray column), and 10 d (filled column) after administration of ACTH. Columns and vertical bars represent mean±S.E.M. (n=8). **Significantly different versus before administration of ACTH (p
