Kensuke Kodama

Administration of antisense DNA for ghrelin causes an antidepressant and anxiolytic response in rats

RATIONALE Ghrelin is a peptide of 28 amino acids found in mammals that increases the release of growth hormone, food intake, and body weight. OBJECTIVES We investigated the relationship between ghrelin and the states of anxiety and depression by giving rats either antisense DNA for ghrelin, scrambled DNA or vehicle into the lateral ventricle of rats. RESULTS In forced swimming tests, rats that received antisense DNA decreased the length of time that they were immobile in the water. Ghrelin antisense oligonucleotides produced an anxiolytic-like effects in the elevated plus maze test, black and white test, or conditioned fear tests. Treatment with antisense DNA for ghrelin significantly decreased rat body weight. No significant effect on general locomotor activity was seen. CONCLUSIONS These results suggest that administration of antisense DNA for ghrelin causes an antidepressant and anxiolytic response in rats.

Ghrelin gene polymorphism is associated with depression, but not panic disorder.

Ghrelin, which was identified for the first time by Kojima et al. in rat stomach, is a novel peptide of 28 amino acids, which acts as endogenous ligand for the growth hormone secretagogue receptor (Kojima et al., 1999; Kojima and Kangawa, 2005). Thus, one function of ghrelin is to increase pituitary release of growth hormone (Arvat et al., 2000). Regional distribution of ghrelin receptors suggests that the peptide could be related to emotional processes. Some researchers reported that both central (e.g. intraventricular) and peripheral (e.g. intraperitoneal) administration of ghrelin is a potent inducer of anxiogenic behavior in mice (Asakawa et al., 2001; Carlini et al., 2002). Similar research indicates that ghrelin induces anxiogenesis in rats. Recently, we reported that administration of antisense DNA for ghrelin causes an antidepressant and anxiolytic response in rats (Kanehisa et al., 2006).

Salivary alpha-amylase and cortisol responsiveness following electrical stimulation stress in major depressive disorder patients.

Major depressive disorder (MDD) is often associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis by chronic stress. In comparison, psychosocial stress-induced activation of salivary α-amylase (sAA) functions as a marker of sympathoadrenal medullary system (SAM) activity. However, in contrast to salivary cortisol, sAA has been less extensively studied in MDD patients. The present study measured sAA and salivary cortisol levels in patients with MDD. The authors determined Profile of Mood State (POMS) and State-Trait anxiety Inventory (STAI) scores, Heart Rate Variability (HRV), and sAA and salivary cortisol levels in 88 patients with MDD and 41 healthy volunteers following the application of electrical stimulation stress. Patients with major depressive disorder were 8 points or more on Hamilton Depression Scale (HAM-D) scores. Tension-Anxiety, Depression-Dejection, Anger-Hostility, Fatigue, and Confusion scores in patients with major depressive disorder were significantly increased compared to healthy controls. In contrast, Vigor scores in patients with MDD were significantly decreased compared with healthy controls. There was no difference in heart rate variability measures between MDD patients and healthy controls. The threshold of electrical stimulation applied in MDD patients was lower than that in healthy controls. SAA levels in female MDD patients were significantly elevated relative to controls both before and after electrical stimulation. Finally, there were no differences in salivary cortisol levels between major depressive patients and controls. In the present study only three time points were explored. Furthermore, the increased secretion of sAA before and after stimulation could allude to an increased responsiveness of novel and uncontrollable situations in patients with MDD. These preliminary results suggest that sAA might be a useful biological marker of MDD.

Low risk of male suicide and lithium in drinking water.

OBJECTIVE Recently, several epidemiologic studies reported that lithium in drinking water may be associated with lower rates of suicide mortality at the population level, but other studies failed to confirm the association. The objective of the present study is to determine whether lithium in drinking water is associated with lower suicide rate after adjustment of potential confounding factors. METHOD From 2010 to 2013, 274 mean lithium levels of 434 lithium samples in drinking water were examined in relation to suicide standardized mortality ratios (SMRs) in 274 municipalities of Kyushu Island in Japan. Weighted least squares regression analysis adjusted for the size of each population was used to investigate the association of lithium levels with suicide SMRs. The associations of lithium levels in drinking water with suicide SMRs (total, male, and female) were investigated adjusting for proportion of elderly people, proportion of 1-person households, proportion of people with college education or more, and proportion of people engaging in primary industry (adjusted model 1), and further adjustment was performed with overall unemployment rate, annual marriage rate, annual mean temperature, and annual postal savings per person (adjusted model 2). RESULTS Lithium levels in drinking water were significantly (β = -.169, P = .019) and inversely associated with male suicide SMRs but not total or female SMRs in the adjusted model 2. CONCLUSIONS The present findings suggest that lithium in drinking water may be associated with the low risk of male suicide in the general population. Further studies are required to confirm these findings and investigate gender differences.

Elevated salivary α-amylase and cortisol levels in unremitted and remitted depressed patients.

Abstract Objective. Major depressive disorder (MDD) is often associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis via chronic stress. Psychosocial stress-induced activation of salivary α-amylase (sAA) represents sympathoadrenal medullary system (SAM) activity, and sAA has become an emerging biomarker for sympathetic nervous system activity. In contrast to salivary cortisol, sAA has been less extensively studied in depressed patients. The present study sought to address this problem by measuring sAA and salivary cortisol levels in patients with major depressive disorder. Methods. The authors recorded Spielberger State-Trait Anxiety Inventory (STAI) scores along with, levels of sAA and salivary cortisol in 28 patients with unremitted major depressive disorder, 43 remitted patients and 103 healthy volunteers. Results. STAI (State or Trait) measurements in unremitted patients with MDD were significantly increased compared with healthy controls and remitted patients. SAA and cortisol levels in unremitted patients were also significantly elevated compared to controls and remitted patients. Finally, sAA levels were significantly correlated with HRSD in unremitted patients with MDD. Conclusion. These preliminary results suggest that sAA may be a state-dependent marker of major depressive disorder in addition to salivary cortisol.

Spatial memory impairment in OLETF rats without cholecystokinin - a receptor.

Cholecystokinin (CCK) is one of the most abundant neurotransmitter peptides in the brain. As Otsuka Long-Evans Tokushima Fatty (OLETF) rats lack CCK-A receptor because of a genetic abnormality, we examined whether learning and memory were impaired in these animals using both Morris water maze (MWM) and step-through type passive avoidance (PA) learning test. In the MWM test, memory impairment was observed in OLETF rats. The number of errors was also significantly higher, and that of the correct choices was significantly lower in OLETF rats compared to the controls [Long-Evans Tokushima Otsuka (LETO)] rats. In PA, OLETF rats did not show facilitating response 24 h after training. From these observations, we concluded that a spatial memory was impaired in the OLETF rats.

Anxiogenic-Like Effect of Corticotropin-Releasing Factor Receptor 2 Antisense Oligonucleotides Infused into Rat Brain

Corticotropin-releasing factor (CRF) is widely distributed in the brain and coordinates behavioural responses to stress. Its receptor subtypes, CRF-R1 and CRF-R2, are expressed in the brain. For this study, we tested the effect of a continuous infusion of CRF-R2 antisense oligonucleotides into the lateral ventricle on anxiety-related behaviours in rats. Our results indicate that CRF-R2 antisense oligonucleotides produced an anxiogenic-like effect in elevated plus maze, black and white box and conditioned fear stress in rats. No significant effect on general locomotor activity was seen. These results indicate that inhibition of CRF-R2 induces an increase in anxiety-related behaviours suggesting an anxiogenic-like effect.

Hyperthymic temperament and brightness judgment in healthy subjects: Involvement of left inferior orbitofrontal cortex

BACKGROUND Hyperthymic temperament has been generally accepted as one of premorbid temperament of bipolar disorders. Since recent several studies indicate an association between illuminance and hyperthymic temperament, it can be hypothesized that more hyperthymic temperament subjects have a different threshold of brightness or darkness perception in comparison with less hyperthymic temperament subjects. METHODS We compared the threshold of brightness and darkness judgment between more and less hyperthymic subjects, and by simultaneously using fMRI we compared activations of whole brain between these subjects by two sample t-test. Furthermore, the association between the activations and hyperthymic temperament scores was analyzed. RESULTS Although there was no significant difference in the threshold of brightness or darkness judgment between more and less hyperthymic subjects, there was a significant difference in activations of the regions including left superior temporal gyrus, left inferior orbitofrontal cortex, left triangular inferior frontal gyrus and left insula between these subjects. Moreover, there was a significantly positive association between a cluster containing left inferior orbitofrontal cortex and hyperthymic temperament scores. The common activated region of these two analyses (categorical and continuous ones) was determined as left inferior orbitofrontal cortex. LIMITATIONS Limitation of the present study is a lack of brightness and darkness preference experiment between more and less hyperthymic subjects. CONCLUSIONS The present findings suggest that the threshold of brightness and darkness judgment is not different between more and less hyperthymic subjects, and that hyperthymic temperament may be associated with left inferior orbitofrontal cortex, which has been reported to be associated with bipolar disorder.

Anxiolytic suppression of repetitive transcranial magnetic stimulation-induced anxiety in the rats

Repetitive transcranial magnetic stimulation (rTMS) is effective for treatment of several psychiatric disorders such as depression and anxiety disorder. However, some reports suggest that rTMS induced anxiety in normal volunteers. Consistent with this observation, we have reported that chronic rTMS induces anxiety in normal rats which was suppressed by chronic treatment, but not acute paroxetine treatment. The current study evaluates rTMS as animal model of anxiety by investigating the effect of rTMS on anxiety behaviors and the ability of standard anxiolytics to block expression of these behaviors. We found that 10-day rTMS induced anxiety in normal rats, as evidenced by expression of anxiety behaviors in the elevated plus-maze. This anxiety was suppressed by acute treatment with diazepam, alprazolam, or buspirone suggesting that chronic rTMS treatment provides a good animal model for anxiety.

A young woman with visual hallucinations, delusions of persecution and a history of performing arson with possible three‐generation Fahr disease

Objective:  Fahr disease (FD) is a rare neurological and psychiatric disorder. The disease is classified by intracranial calcification of the basal ganglia with the globus pallidus region being particularly affected. We examined a young woman with visual hallucinations, delusions of persecution and a history of performing arson with possible third‐generation FD.