Influences of Dopamine D2, D3 Agonist Quinpirole Dosage on Locomotor Activity Measured by Open-Field Test

Park Jeonghyun,Moon Eunsoo,Lim Hyun Ju,Kim Kyungwon,Lee Jung Hyun,Hong Yoo Rha 대한우울조울병학회 2022 우울조울병 Vol.20 No.3

Background: Dopamine D2 and D3 receptor agonist quinpirole have been tried as one of drug-induced bipolar animal models. An open-field test is used to assess locomotor activity related to anxiety. Not many studies have analyzed the effects of quinpirole dosages on locomotor activity. The purpose of this study was to look at the locomotor activity of quinpirole-injected mice in an open-field test. Methods: The open-field test was used to observe the locomotor activities of 28 mice. Quinpirole was administrated at 0.05-5 mg/kg and normal saline were used as a control. The Mann-Whitney U-test was employed to compare the locomotor activities in the quinpirole and control groups. Results: Quinpirole-induced locomotor activities reduced as time elapsed during the first 30 minutes following the injection in most mice, then increased or fluctuated in the later 30 minutes. As the dosage was increased, there was a stronger initial inhibition, followed by a rapid and further increase in the last 30 minutes. Conclusion: This study showed the differential effects of quinpirole-induced locomotor activities depending on dosage, and initial suppression of locomotor activities by quinpirole was observed. Additionally, longitudinal observation of more than 1 hour would be required to look into the biphasic pattern of quinpirole in an animal model.

Quinpirole Increases Melatonin-Augmented Pentobarbital Sleep via Cortical ERK, p38 MAPK, and PKC in Mice

( Sa Ik Hong ),( Seung Hwan Kwon ),( Ji Young Hwang ),( Shi Xun Ma ),( Jee Yeon Seo ),( Yong Hyun Ko ),( Hyoung Chun Kim ),( Seok Yong Lee ),( Choon Gon Jang ) 한국응용약물학회 2016 Biomolecules & Therapeutics(구 응용약물학회지) Vol.24 No.2

Sleep, which is an essential part of human life, is modulated by neurotransmitter systems, including gamma-aminobutyric acid (GABA) and dopamine signaling. However, the mechanisms that initiate and maintain sleep remain obscure. In this study, we investigated the relationship between melatonin (MT) and dopamine D2-like receptor signaling in pentobarbital-induced sleep and the intracellular mechanisms of sleep maintenance in the cerebral cortex. In mice, pentobarbital-induced sleep was augmented by intraperitoneal administration of 30 mg/kg MT. To investigate the relationship between MT and D2-like receptors, we administered quinpirole, a D2-like receptor agonist, to MT- and pentobarbital-treated mice. Quinpirole (1 mg/kg, i.p.) increased the duration of MT-augmented sleep in mice. In addition, locomotor activity analysis showed that neither MT nor quinpirole produced sedative effects when administered alone. In order to understand the mechanisms underlying quinpirole-augmented sleep, we measured protein levels of mitogen-activated protein kinases (MAPKs) and cortical protein kinases related to MT signaling. Treatment with quinpirole or MT activated extracellular-signal-regulated kinase 1 and 2 (ERK1/2), p38 MAPK, and protein kinase C (PKC) in the cerebral cortex, while protein kinase A (PKA) activation was not altered significantly. Taken together, our results show that quinpirole increases the duration of MT-augmented sleep through ERK1/2, p38 MAPK, and PKC signaling. These findings suggest that modulation of D2-like receptors might enhance the effect of MT on sleep.

Quinpirole Increases Melatonin-Augmented Pentobarbital Sleep via Cortical ERK, p38 MAPK, and PKC in Mice

Hong, Sa-Ik,Kwon, Seung-Hwan,Hwang, Ji-Young,Ma, Shi-Xun,Seo, Jee-Yeon,Ko, Yong-Hyun,Kim, Hyoung-Chun,Lee, Seok-Yong,Jang, Choon-Gon The Korean Society of Applied Pharmacology 2016 Biomolecules & Therapeutics(구 응용약물학회지) Vol.24 No.2

Sleep, which is an essential part of human life, is modulated by neurotransmitter systems, including gamma-aminobutyric acid (GABA) and dopamine signaling. However, the mechanisms that initiate and maintain sleep remain obscure. In this study, we investigated the relationship between melatonin (MT) and dopamine D2-like receptor signaling in pentobarbital-induced sleep and the intracellular mechanisms of sleep maintenance in the cerebral cortex. In mice, pentobarbital-induced sleep was augmented by intraperitoneal administration of 30 mg/kg MT. To investigate the relationship between MT and D2-like receptors, we administered quinpirole, a D2-like receptor agonist, to MT- and pentobarbital-treated mice. Quinpirole (1 mg/kg, i.p.) increased the duration of MT-augmented sleep in mice. In addition, locomotor activity analysis showed that neither MT nor quinpirole produced sedative effects when administered alone. In order to understand the mechanisms underlying quinpirole-augmented sleep, we measured protein levels of mitogen-activated protein kinases (MAPKs) and cortical protein kinases related to MT signaling. Treatment with quinpirole or MT activated extracellular-signal-regulated kinase 1 and 2 (ERK1/2), p38 MAPK, and protein kinase C (PKC) in the cerebral cortex, while protein kinase A (PKA) activation was not altered significantly. Taken together, our results show that quinpirole increases the duration of MT-augmented sleep through ERK1/2, p38 MAPK, and PKC signaling. These findings suggest that modulation of D2-like receptors might enhance the effect of MT on sleep.

Delay in the Recovery of Normal Sleep-Wake Cycle after Disruption of the Light-Dark Cycle in Mice: A Bipolar Disorder-Prone Animal Model?

정선화,박제민,문은수,정영인,이병대,이영민,김지훈,Soo Yeon Kim,Hee Jeong Jeong 대한신경정신의학회 2014 PSYCHIATRY INVESTIGATION Vol.11 No.4

Objective Disruption of the circadian rhythm is known as a provoking factor for manic episodes. Individual differences exist in the recovery rate from disruption in the general population. To develop a screening method to detect individuals vulnerable to bipolar disorder, the authors observed the relationship between the recovery of the normal sleep-wake cycle after switching the light-dark (LD) cycle and quinpirole-induced hyperactivity in mice. Methods Sixteen male mice (age of 5 weeks, weight 28–29 gm) were subjected to a circadian rhythm disruption protocol. Sleep-wake behaviors were checked every 5 min for a total duration of 15 days, i.e., 2 days of baseline observations, 3 days of LD cycle changes, and 10 days of recovery. During the dark cycle on the 16th experimental day, their general locomotor activities were measured in an open field for 120 minutes after an injection of quinpirole (0.5 mg/kg, s.c.). Results The individual differences in the recovery rate of the baseline sleep-wake cycle were noted after 3 days of switching the LD cycle. Fifty percent (n=8) of the mice returned to the baseline cycle within 6 days after normalizing the LD cycle (early recovery group). The locomotor activities of mice that failed to recover within 6 days (delayed recovery group) were significantly higher (mean rank= 12.25) than those of the early recovery group (mean rank=4.75, u=62.0, p=0.001, Mann-Whitney U test). Conclusion Given that the quinpirole-induced hyperactivity is an animal model of bipolar disorder, our results suggest individuals who have difficulties in recovery from circadian rhythm disruption may be vulnerable to bipolar disorder.

Protein Kinase C Activity and Delayed Recovery of Sleep-Wake Cycle in Mouse Model of Bipolar Disorder

Eunsoo Moon,Byeong-Moo Choe,Je-Min Park,Young In Chung,Byung Dae Lee,Jae-Hong Park,Young Min Lee,Hee Jeong Jeong,YongJun Cheon,Yoonmi Choi,Jeonghyun Park 대한신경정신의학회 2018 PSYCHIATRY INVESTIGATION Vol.15 No.9

Objective Previous studies reported the delayed recovery group after circadian rhythm disruption in mice showed higher quinpiroleinduced locomotor activity. This study aimed to compare not only Protein Kinase C (PKC) activities in frontal, striatal, hippocampus and cerebellum, but also relative PKC activity ratios among brain regions according to recovery of circadian rhythm. Methods The circadian rhythm disruption protocol was applied to eight-week-old twenty male Institute Cancer Research mice. The circadian rhythm recovery patterns were collected through motor activities measured by Mlog system. Depressive and manic proneness were examined by forced swim test and quinpirole-induced open field test respectively. Enzyme-linked immunosorbent assay was employed to measure PKC activities. Results The delayed recovery group presented greater locomotor activities than the early recovery group (p=0.033). The delayed recovery group had significantly lower frontal PKC activity than the other (p=0.041). The former showed lower frontal/cerebellar PKC activity ratio (p=0.047) but higher striatal/frontal (p=0.038) and hippocampal/frontal (p=0.007) PKC activities ratios than the latter. Conclusion These findings support potential mechanism of delayed recovery after circadian disruption in bipolar animal model could be an alteration of relative PKC activities among mood regulation related brain regions. It is required to investigate the PKC downstream signaling related to the delayed recovery pattern.

Changes of Locomotor Activity by Dopamine D2, D3 Agonist Quinpirole in Mice Using Home-cage Monitoring System

Jeonghyun Park,Eunsoo Moon,Hyun Ju Lim,Kyungwon Kim,Yoo Rha Hong,Jung Hyun Lee 대한정신약물학회 2023 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.21 No.4

Objective: As dopamine is closely linked to locomotor activities, animal studies on locomotor activities using dopaminergic agents were widely done. However, most of animal studies were performed for a short period that there is a lack of longitudinal study on the effects of dopaminergic agents on locomotor activities. This study aimed to examine the longterm effect of a dopamine D2, D3 agonist quinpirole on locomotor activities in mice using a home-cage monitoring system. Methods: The locomotor activities of Institute Cancer Research mice were measured by infrared motion detectors in home-cages under the 12-hour dark and 12-hour light condition for three days after the quinpirole injection. Quinpirole was injected at a concentration of 0.5 mg/kg intraperitoneally in the beginning of the dark phase. The locomotor activities before and after the quinpirole administration were compared by the Wilcoxon signed-rank test and one-way repeated measures ANOVA. Results: After the quinpirole administration, the 24-hour total locomotor activity did not change (p = 0.169), but activities were significantly increased in the 12-hour dark phase sum (p = 0.013) and decreased in the 12-hour light phase sum (p = 0.009). Significant increases in the activities were observed in the dark-light difference (p = 0.005) and dark-light ratio (p = 0.005) as well. Conclusion: This study suggests that quinpirole injection entrains the circadian rest-activity rhythm of locomotor activities. Therefore, quinpirole can be a drug that mediates locomotor activity as a dopamine agonist as well as a modulator of the circadian rhythms.

Delay in Normalization of Disrupted Sleep-Wake Cycle in Mice as a Bipolar Disorder-Prone Animal Model (Bipolar Disorder-Prone Animal Model)

Soo Yeon Kim,Eunsoo Moon,Hee Jeong Jeong,Young Min Lee,Byung Dae Lee,Je-Min Park 대한신경정신의학회 2016 신경정신의학 Vol.55 No.3

Objectives This study was designed to test the hypothesis that delayed recovery from disrupted circadian rhythm is associated with both manic and depressive episodes in bipolar disorder. Methods Twenty-two male mice (age of five weeks, weight 28–30 gm) underwent three days of light-dark cycle disruption and 10 days of recovery phase. Sleep and wake state were checked every five minutes during the entire experimental period. After recovery phase, quinpirole (0.5 mg/kg, s.c.) was injected into the mice and open field locomotor activities were checked. Five days after the open field test, immobility time during the last 4 min in 6 min of forced swimming test was measured. Animals which recovered sleep-wake cycle within six days after light-dark cycle disruption were assigned to the early recovery group (n=14), and those that failed to recover in six days were assigned to the delayed recovery group (n=8). The locomotor activities and the immobility times of the two groups were compared by Mann-Whiney U test at two-tailed significance level of 0.05. Results The locomotor activities of the delayed recovery group were higher (mean rank=16.19) than those of the early recovery group (mean rank=8.82, U=18.5, p=0.008). The immobility times did not differ by recovery time (U=32.0 p=0.110). Conclusion The results suggest that delayed recovery from circadian rhythm disruption raises the risk of manic symptoms rather than depressive symptoms