Ichiyo Matsuzaki

Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior

The hypothalamus plays a central role in the integrated control of feeding and energy homeostasis. We have identified two novel neuropeptides, both derived from the same precursor by proteolytic processing, that bind and activate two closely related (previously) orphan G protein-coupled receptors. These peptides, termed orexin-A and -B, have no significant structural similarities to known families of regulatory peptides. prepro-orexin mRNA and immunoreactive orexin-A are localized in neurons within and around the lateral and posterior hypothalamus in the adult rat brain. When administered centrally to rats, these peptides stimulate food consumption. prepro-orexin mRNA level is up-regulated upon fasting, suggesting a physiological role for the peptides as mediators in the central feedback mechanism that regulates feeding behavior.

Orexin-induced food intake involves neuropeptide Y pathway

Orexins (orexin-A and -B) are recently identified neuropeptides, which are thought to be implicated in the regulation of feeding behavior. We used a NPY-Y1 receptor specific antagonist, BIBO3304, to examine whether NPY is involved in orexin-induced feeding behavior. Intracerebroventricular administration of orexin-A (10 nmol) induced food intake in rats (food intake for 3 h; vehicle 0.3+/-0.2 g vs. orexin-A 10 nmol, 4.0+/-0.5 g, n=4). Orexin-induced feeding behavior was partially inhibited by prior administration of BIBO3304 (3 h food intake: orexin-A 10 nmol, 4.0+/-0.5 g vs. BIBO3304 (60 microgram) + orexin-A 10 nmol, 2.2+/-0.2 g, n=4). A low dose of BIBO3304 (30 microgram) did not show a significant inhibitory effect. BIBO3457, an inactive enantiomer, used as a negative control, did not show any inhibitory effect on orexin-A-induced feeding behavior. Fos expression was observed in NPY-containing neurons in the arcuate nucleus 1 h after orexin-A (10 nmol) was administered intracerebroventricularly (control 0.3+/-0.08%, orexin-A 10.2+/-0.8%, n=5 rats/group). These observations suggest that NPY is involved in orexin-induced feeding behavior. However, BIBO3304 did not completely abolish the effect of orexin-A. These results suggest that orexin-A elicits feeding behavior partially via the NPY pathway. The NPY system could be the one of downstream pathways by which orexin-A induces feeding behavior. Another pathway may also be involved in orexin-A-induced feeding behavior, because BIBO3304 did not completely abolish orexin-A-induced feeding behavior.

Orexins/hypocretins regulate drinking behaviour.

Orexin/hypocretins are recently identified neuropeptides which regulate feeding behaviour. We found orexins increased water intake when administrated intracerebroventricularly to rats. The effect of orexin-A was more potent as compared with orexin-B, suggesting the possible involvement of OX(1) receptor. The efficacy of orexin-A was almost comparable with that of angiotensin II, and the effect lasted more than 3 h. Prepro-orexin mRNA level was up-regulated when rats were deprived of water. Orexin-immunoreactive varicose axons were observed in the subfornical organ and area postrema, regions implicated in drinking behaviour. These observations suggest a physiological role for orexin as mediators that regulate drinking behaviour.

The effects of intracerebroventricularly injected corticotropin-releasing factor (CRF) on the central nervous system : behavioural and biochemical studies

Intracerebroventricularly (ICV) administered corticotropin-releasing factor (CRF) produces behavioural activation in rats. The present study was designed to investigate the effects of ICV administered CRF on not only locomotor activity, but also the turnover rates of dopamine (DA) and norepinephrine (NE) in various discrete brain regions in rats. ICV administration of 1 microgram CRF produced a significant increase in locomotor activity, while ICV administration of 10 micrograms CRF caused slow stereotypy with prominent grooming. The 3,4-dihydroxyphenylacetic acid/DA ratio, e.g. DA utilization, was increased in the frontal cortex (FC), striatum, hippocampus (HIPP) and amygdala. DA utilization in the FC increased in a dose dependent manner, suggesting that the hyperactivity of the mesocortical DA system is relevant to the grooming response. The 3-methoxy-4-hydroxy-phenylglycol/NE ratio was increased in the FC and HIPP, indicating the involvement of the dorsal NE pathway in ICV CRF-induced behavioural changes in rats. These findings are discussed in connection with the hypothesis that CRF produces behavioural changes consistent with increasing emotionality, especially anxiety, and may serve as a neuroendocrine modulator of stress-enhanced behaviour.

Psychology and culture during long-duration space missions ☆

The International Academy of Astronautics Study Group on Psychology and Culture in LongDuration Space Missions first convened in May 2003, at the 14 Humans in Space Symposium in Banff, Canada. After this initial meeting to define the group’s task, members divided into subcommittees and worked on drafts of sections of the document over email. The group reconvened in person several times to coordinate the structure of the paper. These sessions occurred at scientific meetings where many of the members were present. The study group formally convened in 2003 at the International Astronautical Congress (IAC) in Bremen and at the Institute for Biomedical Problems 40 Anniversary Symposium in Moscow. In 2004 it convened at the IAC in Vancouver and at the Annual Meeting of the Aerospace Medical Association (AsMA) in Anchorage. In 2005 it convened at the Humans In Space Symposium in Graz, at the IAC in Fukuoka, and at the AsMA Meeting in Kansas City. In 2006 the group worked over e-mail and will convene at the IAC in Valencia after the paper is finished in order to debrief and set out plans for future work. The objective of this report is twofold: a) to describe the current knowledge of cultural, psychological, psychiatric, cognitive, and interpersonal issues that are relevant to the behavior and performance of astronaut crews and ground support personnel; and b) to make recommendations for future human space missions, including both transit and planetary surface operations on the Moon, Mars, and beyond. The focus will be on long-duration missions lasting at least six weeks, when important psychological and interpersonal factors begin to take their toll on crewmembers. This information is designed to provide guidelines for astronaut selection and training, in-flight monitoring and support, and post-flight recovery and re-adaptation. After a consideration of Cultural Issues, which impact on the entire report, four main sections follow: Personality, Coping, and Adaptation; Behavioral Health and Psychiatry; Cognition and Complex Performance Skills; and Interpersonal and Organizational Issues. For each of these sections, there is a review of general issues; implications for mission operations in terms of crew selection, training, monitoring and support, and re-adaptation to Earth; and operational and research recommendations involving future missions to Earth orbit, the lunar surface, or to Mars and beyond.

The association between intravenous haloperidol and prolonged QT interval.

Although intravenous haloperidol (HAL) is an effective medication that is often prescribed to treat agitation, several instances of torsade de pointes or prolonged QT interval have been reported. To investigate the association between intravenous HAL and QT prolongation and between intravenous HAL and ventricular tachyarrhythmia, a cross-sectional cohort study was performed that included measuring corrected QT intervals (QTc) on an emergency basis before intravenous HAL and continuously monitoring electrocardiographic (ECG) findings after intravenous HAL. During a 2-month period, 47 patients received intravenous injections to control psychotic disruptive behavior. According to clinical practice, patients were divided as follows. The FZ-alone group was treated with intravenous flunitrazepam (FZ), and the FZ-plus-HAL group received intravenous FZ followed by intravenous HAL. Although the difference in the mean QTc immediately after intravenous FZ between the two groups was not significant, the mean QTc after 8 hours in the FZ-plus-HAL group was longer than that in the FZ-alone group (p < 0.001). Four patients in the FZ-plus-HAL group had a QTc of more than 500 msec after 8 hours. The change in QTc during 8 hours significantly differed between the two groups (t = 2.64, p > 0.05). Furthermore, the change in QTc was moderately correlated with the dose of intravenous HAL, as evidenced by a coefficient of correlation of 0.48 (p < 0.001). However, ventricular tachyarrhythmia was not detected among 307 patients within a 1-year period, although the ECG was continuously monitored for at least 8 hours after intravenous HAL. The modest nature of QTc prolongation and the apparent absence of ventricular tachyarrhythmia under continuous ECG monitoring indicate that QTc prolongation associated with intravenous HAL is not necessarily dangerous. However, in an emergency situation, clinicians cannot exclude patients predisposed to torsade de pointes, such as those with inherited ion channel disorders. Therefore, clinicians should be aware of the association between intravenous HAL and QT prolongation.

Nonthermal effects of mobile-phone frequency microwaves on uteroplacental functions in pregnant rats

Exposure to high-density microwaves can cause detrimental effects on the testis, eye, and other tissues, and induce significant biologic changes through thermal actions. To examine nonthermal effect of continuous wave (CW) 915MHz microwaves used in cellular phones, we compared the effects of microwaves with those of heat. Thirty-six pregnant rats were assigned to six groups: rats exposed to microwaves at 0.6 or 3mW/cm(2) incident power density at 915MHz for 90min, rats immersed in water at 38 or 40 degrees C, which induces about the same increase in colonic temperature of 1.0 or 3.5 degrees C as 0.6 or 3mW/cm(2) microwaves, respectively; rats immersed in water at 34 degrees C, which is considered to be thermoneutral; and control rats. We identified significant differences in the uteroplacental circulation, and in placental endocrine and immune functions between pregnant rats immersed in water at 34 and 38 degrees C, but not between rats immersed at 38 degrees C and those exposed to microwaves at 0.6mW/cm(2). By contrast, we observed significant decreases in uteroplacental blood flow and estradiol in rats exposed to microwaves at 3mW/cm(2) as compared with those immersed in water at 40 degrees C. These results suggest microwaves at 0.6mW/cm(2) at 915MHz, equal to a specific absorption rate (SAR) of 0.4W/kg, which is the maximum permissible exposure level recommended by the American National Standards Institute (ANSI), do not exert nonthermal effects on blood estradiol and progesterone, on splenic natural killer cell activity, on the uteroplacental circulation.

Involvement of the serotonergic system in orexin-induced behavioral alterations in rats

We have demonstrated involvement of the serotonergic system in orexin-induced behavioral responses in rats. Orexin-A and -B (hypocretin-1 and -2) significantly increased total locomotor activity when administered centrally. They also induced behavioral alterations; increasing grooming, face washing and wet dog shaking in rats. Haloperidol inhibited orexin-induced hyperlocomotion and these behavioral alterations. Serotonin antagonists, ritanserin and metergoline, did not attenuate orexin-induced hyperlocomotion but partly inhibited orexin-induced behavioral alterations. These results suggest that the dopaminergic system might be involved in orexin-induced hyperlocomotion, while both the serotonergic system as well as the dopaminergic system might be involved in orexin-induced behavioral responses.

Psychological Factors Including Sense of Coherence and Some Lifestyles are Related to General Health Questionnaire-12 (GHQ-12) in Elderly Workers in Japan

ObjectivesThe number of elderly workers has also been increasing and poor psychological well-being in elderly workers has been reported. The aim of this study is to elucidate the factors that are related to poor psychological well-being in elderly workers.MethodsWe administered General Health Questionnaire-12 (GHQ-12) as an indicator of psychological well-being to 330 male elderly workers in the age range of 50–69, and analyzed different psychological factors, namely sense of coherence (SOC), and physical and lifestyle variables such as blood pressure, serum total cholesterol, smoking frequency, alcohol intake, exercise frequency, and body mass index (BMI) that are related to GHQ-12.ResultsWhen the cut-off point of GHQ-12 was 2/3, 97 workers who showed high GHQ-12 score were classified as one group having poor psychological well-being. A statistically significantly lower SOC score, higher stress score, lower frequency of exercise, higher smoking score and higher BMI, but not longer working hours or higher shift work score in the workers with higher GHQ-12 scores were observed than in the workers with normal GHQ-12 scores. Multiple logistic regression analysis showed that the low SCO score, low frequency of exercise, high smoking frequency and high BMI significantly contributed to the high GHQ-12 score.ConclusionsA low SOC score in elderly workers is assumed to be directly related to poor psychological well-being, or via the development of lifestyle problems such as lack of exercise, obesity, and smoking in elderly workers. This assumption must be confirmed by conducting future intervention studies on lifestyle.

The effect of stress‐related factors on mental health status among resident doctors in Japan

Medical Education 2010: 44: 826–834