Kyoji Kojima

Phenytoin intoxication induced by fluvoxamine.

A patient had phenytoin intoxication after administration of fluvoxamine, a selective serotonin reuptake inhibitor. The serum concentration of phenytoin increased dramatically from 16.6 to 49.1 microg/mL when fluvoxamine was coadministered, although the daily dosage of phenytoin and other drugs had not changed. During phenytoin and fluvoxamine treatment, ataxia, a typical side effect of phenytoin, was observed. The genotypes of CYP2C9 and 2C19, the enzymes responsible for phenytoin metabolism, were homozygous for the wild-type alleles (CYP2C9*1/*1 and 2C19*1/ *1). The interaction may be a result of inhibition of both CYP2C9 and 2C19 by fluvoxamine.

Changes in the leukocyte distribution and surface expression of adhesion molecules induced by hypothalamic stimulation in the cat

Emotions and the neuroendocrine system are known to affect leukocyte distribution. However, there have so far been few reports on the relationship between hypothalamically induced emotional behavior and the endocrine-immune response. We previously reported changes in the leukocyte distribution and adhesion molecules induced by anteromedial hypothalamus stimulation (AH stimulation), which elicits restlessness behaviors in the cat. In this study, we examined ventromedial hypothalamus stimulation (VMH stimulation), which elicits threat behaviors. In addition, the endocrine responses after VMH stimulation were evaluated. VMH stimulation as well as AH stimulation induced elevations of plasma cortisol and epinephrine levels and granulocytosis and lymphopenia. In contrast, VMH stimulation induced only an elevation of plasma norepinephrine and elicited an opposite pattern of CD62L expression on the leukocyte subpopulations. The different endocrine-immunological reactions between VMH stimulation and AH stimulation were thus associated with different types of behavioral responses.

The relation of emotional behavior to plasma catecholamines, cortisol and ventricular arrhythmia

Hypothalamic stimulation applied through chronically implanted electrodes elicits several kinds of emotional behavior in conscious cats. We chose 3 kinds of emotional behavior, i.e., restlessness, threat and searching-biting. Under lightly anesthetized condition, we examined the changes of E, NE, DA and cortisol levels in arterial plasma and the cardiovascular responses (changes of systolic and diastolic blood pressure, heart rate and the occurrence of poststimulus ventricular arrhythmia) associated with electrical stimulation of specific sites within the hypothalamus. Both in restlessness and threat groups, elevation in systolic blood pressure was significantly greater and also the occurrence of ventricular arrhythmia and elevation in diastolic blood pressure tended to be greater than in the searching-biting group. Plasma E, NE, DA and cortisol increased significantly in restlessness and threat groups but remained unchanged in searching-biting and control groups. The ratios of changed values in catecholamines: delta E/delta NE, delta E/delta DA or delta NE/delta DA were not significantly different between any groups of emotional behavior. Furthermore, in the restlessness group, delta E, delta NE and delta DA all showed significant correlation with both the number of ventricular arrhythmia and changes of diastolic blood pressure; and the number of ventricular arrhythmia showed significant correlation with both the changes of diastolic blood pressure and heart rate. None of these correlations was observed in the threat or searching-biting group. These results suggested that restlessness and threat behaviors were more closely related to stress response than searching-biting behavior in cats. The differences in the endocrine and cardiovascular responses between restlessness and threat behavior were also discussed in the paper.

Relation of emotional behaviors to urine catecholamines and cortisol

We examined changes of epinephrine, norepinephrine, and cortisol levels in 24-h urine accompanying emotional behavior in cats such as restlessness, threat, and quiet biting attack elicited by electrical stimulation of specific sites within the hypothalamus. Although norepinephrine remained unchanged with restlessness but increased with threat, elevation of epinephrine and cortisol levels was common to restlessness and threat. No significant changes in these hormonal levels were seen with quiet biting attack and control. Therefore, it was suggested that emotional behaviors such as restlessness and threat are more closely related to emotional stress than quiet biting attack in cats.

Effects of both the emotional behavior and feeding conditions on the circulating plasma volume and plasma glucose levels in cats

Influence of hypothalamically induced emotional behavior on the circulating plasma volume, plasma levels of glucose, epinephrine (E), norepinephrine (NE), dopamine (DA) and cortisol were examined in awake cats under both fasted and fed conditions. Restlessness was evoked intermittently for 6 h by electrical stimulation of the anteromedial hypothalamus (AMH). Blood was sampled immediately before, 1 h after and 6 h after the start of stimulation. Changes in the plasma volume was calculated by changes of hemoglobin (Hb) and hematocrit (Ht). As the control group, another 7 cats with electrodes implanted but unstimulated were identically treated under both fasted and fed conditions. Both E and glucose levels in restlessness group once markedly increased after 1 h and then tended to decrease after 6 h, whereas NE levels in restlessness group increased after 1 h and further increased after 6 h, whether cats were fasted or fed. DA levels increased under the fasted condition of restlessness. The cortisol level markedly increased in both fasted and fed restlessness groups. The plasma volume in control group increased under the fed condition, while in restlessness group it decreased remarkably and tended to decrease more in a fasted state than in a fed state. These results indicated that AMH induced restlessness elicited marked sympatho-adrenal activation, hyperglycemia and hemoconcentration, whether cats were fasted or fed. Relationship among such responses, and the difference in responses between fasted and fed conditions were also discussed in the paper.

Hypothalamically induced emotional behavior and immunological changes in the cat

Abstract Numerous animal studies on the correlation between stress and immunity have been performed but few such studies have been made concerning the relationship between various kinds of stress‐related emotional behavior and immunological changes. Electrical stimulation of the hypothalamus in cats elicits various emotional behaviors such as restlessness, defensive attack, defensive retreat and quiet biting attack. We examined changes in the lymphocyte proliferative responses and plasma cortisol level which accompanied such emotional behavior. A significant increase in plasma cortisol was observed in the restlessness, defensive attack and defensive retreat groups, but not in the quiet biting attack or non‐response (control) groups. A significant increase in the lymphocyte proliferative responses to phytohemagglutinin (PHA) was observed in the restlessness and defensive attack groups but not in the defensive retreat, quiet biting attack or non‐response groups. These results suggest that various kinds of emotional behavior appear to be differentially correlated with the lymphocyte proliferative responses, while also being differentially correlated with the plasma cortisol concentration. Because the changes in lymphocyte responses and plasma cortisol did not always completely correlate with one another, the changes in the lymphocyte responses are not considered to be influenced by plasma cortisol alone.

The Effects of a Switch-Off Response Accompanied by Hypothalamically Induced Restlessness on Immunoendocrinological Changes in Cats

Electrical stimulation of the anterior hypothalamus in cats elicits a behavior called restlessness. When a switch is available for the cats to shut off the electrical stimulation, the cats learn to turn off the stimulation (switch-off response; SOR). In this study, we examined the relationship between the SOR and immunoendocrinological alterations. First of all, an escapable stimulation, in which cats could turn off the stimulation, was applied (escapable condition; EC). One month later, inescapable stimulation was delivered under the same conditions except for the fact that the cats could not turn off the stimulation (inescapable condition; IC). A behavioral analysis revealed that unstable patterns of behavior and a reduction in motor activity were observed in IC compared with those in EC. Furthermore, no significant changes in peripheral leukocytes were observed, while plasma epinephrine and cortisol transiently increased after the series of stimulations, but immediately decreased after the end of the stimulation in EC. On the other hand, there was a greater and prolonged increase in the number of peripheral granulocytes and the plasma levels of epinephrine and cortisol from 1 to 2 h after the stimulation until the end of the experiment in IC. Regarding the number of peripheral lymphocytes, CD4+ or CD8+ lymphocytes and the CD4+ to CD8+ ratio, no significant differences were found between EC and IC. These results suggest that the inability to escape from the aversive stimulation caused a decrease in movement and a prolonged alteration of the immune and endocrine systems, as is often observed in learned helplessness.

Effects of hypothalamically elicited emotional behaviors on the plasma levels of estradiol and IGF-1.

We examined changes in the plasma levels of estradiol (E2), insulin-like growth factor-1 (IGF-1), ACTH, cortisol and catecholamines accompanying various kinds of hypothalamically elicited emotional behaviors in female cats. The emotional behaviors consisting of restlessness, threat and searching-biting (S-B) were elicited intermittently for 6 h by electrical stimulation of the anterior hypothalamus (AH), ventromedial hypothalamus (VMH) and lateral hypothalamus (LH), respectively, in awake and free-moving conditions. The blood was sampled three times immediately before, 1 h after and 6 h after the start of stimulation. The plasma levels of ACTH, cortisol and catecholamines significantly increased in both restlessness and threat behaviors, whereas in the S-B behavior, the ACTH level significantly increased, while the cortisol level showed a slight nonsignificant increase. No changes were observed in the plasma catecholamine levels in the S-B behavior. The plasma E2 level significantly increased in threat behavior after 1 and 6 h of stimulation compared to the prestimulation levels, and the level also increased in comparison to the control group after 1 h. In contrast, the restlessness and S-B behaviors had little or no effect on the E2 level. No significant changes were observed in the plasma levels of IGF-1 in all behavior groups. These findings suggest that various hypothalamically elicited emotional behaviors have differential effects on the plasma E2, but not on the IGF-1 levels. Therefore, E2 and IGF-1 are regulated independently of each other.