Isao Fujii

Rapid desensitization of serotonin 5-HT2C receptor-stimulated intracellular calcium mobilization in CHO cells transfected with cloned human 5-HT2C receptors

Abstract: Serotonin 5‐HT2C receptor‐mediated intracellular Ca2+ mobilization was investigated in Chinese hamster ovary (CHO) cells transfected with 5‐HT2C receptors. Fura‐2 acetoxymethyl ester was used to investigate the regulation of 5‐HT2C receptor function. CHO cells, transfected with a cDNA clone for the 5‐HT2C receptor, expressed 287 fmol/mg of the receptor protein as determined by mianserin‐sensitive [3H]mesulergine binding (KD = 0.49 nM). The addition of 5‐HT mobilized intracellular Ca2+ in a dose‐dependent fashion, ranging from a basal level of 99 ± 1.8 up to 379 ± 18 nM, with an EC50 value for 5‐HT of 0.029 µM. Exposure to 5‐HT, 1‐(3‐chlorophenyl)piperazine dihydrochloride (a 5‐HT2C agonist), and 1‐(4‐iodo‐2,5‐dimethoxyphenyl)‐2‐aminopropane (a 5‐HT2C and 5‐HT2A agonist) resulted in increased intracellular Ca2+ levels. Mianserin, mesulergine, ritanserin, and ketanserin each blocked 5‐HT‐mediated intracellular Ca2+ mobilization more effectively than spiperone. The receptor was rapidly desensitized by preexposure to 5‐HT in a time‐ and concentration‐dependent manner. Mezerein and phorbol 12‐myristate 13‐acetate, protein kinase C activators, weakly inhibited the intracellular Ca2+ mobilization induced by 10 µM 5‐HT. Furthermore, the protein kinase C inhibitor H‐7 partially prevented the protein kinase C activator‐induced inhibition of the 5‐HT‐mediated increase in intracellular Ca2+ concentration. The desensitization induced by pretreatment with 5‐HT was blocked by W‐7, added in conjunction with 5‐HT, and partially inhibited by W‐5, a nonselective inhibitor of protein kinases and weak analogue of W‐7. Therefore, the 5‐HT2C receptor may be connected with protein kinase C and calcium/calmodulin turnover. These results suggest that 5‐HT2C receptor activation mobilizes Ca2+ in CHO cells and that the acute desensitization of the receptor may be due to calmodulin kinase‐mediated feedback.

CCK-4-induced calcium mobilization in T cells is enhanced in panic disorder.

Abstract: We investigated the effects of brain cholecystokinin (CCK) receptors on the intracellular calcium concentration and protein kinase C in human T cells. CCK‐4 produced a transient increase in calcium in the absence of extracellular calcium. CCK‐B agonists stimulated calcium mobilization in a dose‐dependent manner in T cells. CCK‐B antagonists suppressed CCK‐4‐induced calcium mobilization more potently than CCK‐A antagonist. The recovery of desensitization of the CCK‐4‐induced response was delayed by a phosphoserine/phosphothreonine phosphatase inhibitor, calyculin A. The responsiveness to CCK‐4 was also reduced by phorbol 12,13‐dibutyrate (PDBu), and this effect of PDBu was abolished completely by preincubation with staurosporine. CCK‐4‐induced calcium mobilization was too small to attribute the desensitization to the protein kinase C transduction pathway. T cells from patients with untreated panic disorder exhibited significantly higher cholecystokinin‐4‐induced calcium mobilization than those from healthy controls or patients with treated panic disorder. These results suggest that cholecystokinin‐B receptor function in T cells of patients with panic disorder is enhanced. Cholecystokinin‐4‐induced calcium mobilization in T cells may be state dependent and useful as a biological marker of panic disorder.

Cholecystokinin tetrapeptide-induced calcium mobilization in T cells of patients with panic disorder, major depression, or schizophrenia

The localization of cholecystokinin in the brain has accelerated research efforts to define this biochemicals functional role in the central nervous system. The idea of cholecystokinin as a mediator of anxiety originated from electrophysiological experiments (Bradwejn and de Montigny 1984). Benzodiazepine antagonized cholecystokinin-8S-induced excitation of hippocampal pyramidal neurons in rats. This effect was reversed by pretreatment with the benzodiazepine receptor antagonist flumazenil (Csonka et al 1988). Recently, cholecystokinin-tetrapeptide (CCK-4) has been reported to have anxiogenic effects in humans. Intravenous injections of CCK-4 induced symptoms comparable to those of a panic attack (de Montigny 1989). CCK-8S-induced hippocampal pyramidal cell excitation was attenuated by benzodiazepines, but not by meprobamate or naloxone. In a double-blind study, patients were challenged with 50 ixg CCK-4 or saline on separate occasions (Bradwejn 1990). All patients panicked after administration of CCK-4, whereas none of the subjects panicked after receiving saline. The data indicated that patients with panic disorder have an increased sensitivity to CCK-4 (Bradwejn et al 1991). These findings may reflect a neurobiochemical range in CCK in panic disorder. It has been suggested that CCK receptor

Serum cholesterol levels in patients with panic disorders: A comparison with major depression and schizophrenia

Abstract Results of several long‐term follow‐up studies suggest that mortality due to cardiovascular diseases is high in males with panic disorder (PD). Based on these data, various studies have been undertaken to determine the relationship between PD and total cholesterol (TC) levels; however the results obtained so far have not been consistent. We compared TC levels in 46 PD patients to those in 46 sex, age, smoking and alcohol consumption matched patients with major depression and 46 matched patients with schizophrenia. The relationship between TC and the severity of PD was investigated, and before‐ and after‐treatment TC change was compared. TC levels were significantly higher in the PD group than in the other groups, regardless of sex. The severity of PD was not correlated with TC levels. TC levels did not decrease in remitted PD patients. These findings suggest that relatively high TC levels in PD patients are attributable to endogenous disease‐specific factors. Clinicians should pay close attention to the correlation between high mortality due to cardiovascular diseases and relatively high TC levels in male PD patients.

The Sequence of Panic Symptoms

Abstract: For phenomenological elucidation of panic attacks, 26: patients with panic attacks were requested to name the panic symptoms in order of their occurrence and specify the patterns of their abatement. Panic symptoms were found to be classifiable into three categories: early symptoms consisting of dizziness or faintness, palpitations, and sweating; intermediate symptoms dyspnea, nausea or abdominal distress, flush or chills, chest pain or discomfort, shaking, and choking; late symptoms paresthesias, fear of dying, and fear of going crazy. Panic symptoms disappeared in 61.6% irrespective of the sequence of their occurrence. Twenty‐one patients were interviewed about the experience of nocturnal panic attacks, and 23.8% experienced them. These findings suggest that fear is caused by sudden physical abnormality triggered by some biological factors.

Serotonin syndrome during clomipramine monotherapy: Comparison of two diagnostic criteria

Abstract Incidence of serotonin syndrome was determined by two different diagnostic criteria during clomipramine monotherapy. Incidence, determined by Sternbachs criteria, was 12.1% (8/66 patients), and that determined by the criteria of Dursun et al. was 3.0% (2/66 patients). The two patients who met the latter criteria also met the former criteria. The lower incidence with the latter was attributable to the fact that it does not include certain symptoms, such as tremors and diaphoresis, which are included in the former, and were seen in a relatively large number of patients; as well as the fact that the latter more strictly define certain symptoms. Both criteria have pros and cons. Sternbachs diagnostic criteria make it possible to diagnose serotonin syndrome in a wider range of patients, but they sometimes make it difficult to make differential diagnosis in the presence of certain limited symptoms. In contrast, the criteria of Dursun et al. may make a more accurate diagnosis possible, though only in severe cases.

Relationship between SCL-90, Maudsley Personality Inventory and CCK4-induced intracellular calcium response in T cells

This study examined the relationship between the Symptom Checklist 90 (SCL-90), Maudsley Personality Inventory (MPI) and cholecystokinin 4 (CCK4)-induced intracellular calcium response in T cells. Fifty-two normal volunteers were 37 males and 15 females; they ranged in age from 23 to 44 years. Measures included CCK4-induced intracellular calcium response in T cells, SCL-90 scores, and MPI. Paranoid ideation and interpersonal sensitivity in SCL-90 showed a significant negative association with CCK4-induced intracellular calcium response. Absent were sex differences and extroversion and neuroticism correlations. There were no significant differences between men and women in SCL-90 or MPI scores. There was no correlation among extroversion and neuroticism and CCK4-induced intracellular calcium response. CCKB receptor function might play a role in paranoid ideation and interpersonal sensitivity.

Coping behavior in patients with panic disorder

Abstract  The purpose of the present paper was to investigate the role of coping behavior in patients with panic disorder (PD). This was done by evaluating three items of coping behavior (seeking of social support, wishful thinking and avoidance) in the Ways of Coping Checklist. The subjects consisted of 30 patients with PD (26 with agoraphobia). Coping behavior and the severity of PD was investigated at baseline and at 24 months (the final outcome). At baseline there were no gender differences in coping behavior. The severity of panic attacks significantly correlated with that of agoraphobia. The baseline severity of PD (panic attacks and agoraphobia) did not correlate with coping behavior. At the outcome assessment there was no significant correlation between the severity of panic attack and coping behavior. The severity of agoraphobia at final outcome and the coping behavior (seeking of social support) at baseline were significantly correlated. In the group that had remission in agoraphobia (the good outcome group), the severity of agoraphobia at baseline was significantly lower and the seeking of social support coping behavior was significantly higher than that of the poor outcome group. No significant difference in panic attack severity was noted between the good and poor outcome groups. Discriminant analysis revealed that seeking of social support coping behavior was a significant discriminant factor of agoraphobia. Although these are preliminary data, special coping behavior might be related to improvement of agoraphobia in patients with PD.

Panic Disorder and Secondary Depression

nosis, the art of neuroleptics and the therapeutic course about his case, our personal computer program can suggest these points by inputting the age, sex and symptoms. At first the computer searches the nearer cases from about 1,250 cases, collects the information about the chosen cases and analyzes the information. This system is the fuzzy expert system for adolescent psychiatry on the basis of our therapeutic experiences. As for the discussion, we compared the diagnosis between our system, DSM-111-R and ICD10.