Ariyuki Kagaya

Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain

Abstract. Rationale: Lithium is the most widely prescribed mood stabilizer, but the precise mechanism of lithium is unresolved. Objective: We examine the effects of the administration of therapeutically relevant concentrations of lithium on the expression of brain-derived neurotrophic factor (BDNF) and its receptor, Trkxa0B, as well as glia-derived neurotrophic factor (GDNF) and its receptors, RET and GDNFR-alpha, in the rat brain. In addition, we also examined the effect of another well-prescribed mood stabilizer, valproate, on the expression of BDNF and GDNF. Methods: Rats were kept on a 0.2% lithium carbonate-containing diet for 1, 7, 14, or 28xa0days or treated with valproate (400xa0mg/kg per day i.p.) for 1 or 14xa0days. After the brains were rapidly removed, the levels of BDNF, GDNF, and their receptors were measured by ELISA or western blot analysis. Results: Chronic lithium treatment for 14 and 28xa0days significantly increased the expression of BDNF in the hippocampus and temporal cortex. In addition, chronic lithium treatment for 14xa0days significantly increased the expression of BDNF in the frontal cortex. In contrast, acute or chronic dietary lithium treatment did not alter GDNF expression in these brain regions. In addition, acute or chronic lithium treatments did not change the levels of Trkxa0B, RET, or GDNFR-alpha immunoreactivity. As well as lithium, repeated administration of valproate also increased the expression of BDNF in the frontal cortex and hippocampus. Conclusions: Our results suggest that the chronic administration of mood stabilizers may produce a neurotrophic effect mediated by the upregulation of BDNF in the rat brain.

Neurotrophic Action of Interleukin 3 and Granulocyte-Macrophage Colony-Stimulating Factor on Murine Sympathetic Neurons

We investigated neurotrophic effects of interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on cultured sympathetic neurons obtained from mouse superior cervical ganglia. After 1 day of culture with physiological concentrations of mouse recombinant IL-3 and GM-CSF, the numbers of process-bearing neurons were increased. Maximum responses were elicited by 10 U/ml IL-3 and 1 U/ml GM-CSF, which were equivalent to the action of a submaximal dose (5 ng/ml) of nerve growth factor (NGF). The effects of IL-3 and GM-CSF were completely blocked by their corresponding antibodies, but not by anti-NGF, indicting their action is specific and completely independent of NGF. IL-3 and, to a lesser extent, GM-CSF were also able to protect NGF-differentiated neurons from apoptotic cell death caused by NGF withdrawal. The mitogen-activated protein (MAP) kinase signal transduction pathway is known to be involved in action of IL-3 and GM-CSF on hemopoietic cells, and thus we examined the participation of this pathway in the neurotrophic activities of IL-3 and GM-CSF. IL-3 and GM-CSF stimulation of the differentiated neurons was found to result in a rapid elevation of MAP kinase activity, and PD98059, an inhibitor of MAP kinase kinase activity, blocked both the neuritogenic and neuroprotective effects of IL-3 and GM-CSF. Immunocytochemical studies showed that IL-3 and GM-CSF receptors were present on the differentiated neurons. Thus, IL-3 and GM-CSF appear to be able to stimulate sympathetic nerve growth, via specific cytokine receptors on neurons, which lead to activation of the MAP kinase pathway that then mediates the observed neurotrophic effects.

The effects of antidepressant drug treatments on activator protein-1 binding activity in the rat brain.

Since a long-term administration of antidepressant drugs and mood stabilizers is required in the treatment of mood disorders, the regulation of gene expression by these drugs that is mediated by transcription factors, such as activator protein-1 (AP-1) complex, may play an important role in the therapeutic action. In this study, the authors investigated the influence of lithium, antidepressant drugs and stress on AP-1 binding activity in the rat brain. In addition, we examined pretreatment with these drugs on the expression of AP-1 binding activity in response to stress. A gel shift assay was used to measure the levels of AP-1 binding activity. Our results indicate that neither acute nor chronic treatment with antidepressant drugs affects in AP-1 binding activity in the rat frontal cortex or hippocampus. However, the authors found that acute restraint stress for 90 min upregulated the induction of AP-1 binding activity in the rat frontal cortex. In addition, chronic pretreatment with imipramine, but not lithium or paroxetine, downregulated the induction of AP-1 binding activity in response to acute restraint stress in the frontal cortex. The functional classification of antidepressant drugs based on the downregulation of restraint stress-induced AP-1 binding activity may contribute to the advances in our understanding of the pathogenesis of depression.

Effect of lithium carbonate on the enhancement of serotonin 2A receptor elicited by dexamethasone

The purpose of this study was to investigate whether chronic dexamethasone (Dex) administration induces serotonin (5-HT) 2A receptor supersensitivity and if chronic lithium carbonate (Li) administration contributes to the normalization of 5-HT2A receptor supersensitivity induced by Dex in rat brain. We investigated the effects of a 14-day administration of Dex and/or Li on changes in body weight (BW), on plasma corticosterone levels, on plasma lithium levels, on 5-HT2A receptor binding sites, and on (±)-1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane (DOI)-induced wet dog shake (WDS), which is mediated by 5-HT2A receptor in rats. Dex significantly reduced the BW of rats. Li did not have any effect on BW gain and did not prevent the BW loss induced by Dex. The plasma corticosterone levels of rats treated with Dex were too low to be detected. Li did not have any effect on corticosterone levels and did not prevent the decrease in the corticosterone levels induced by Dex. Six hours after the last treatment, the plasma lithium levels of rats treated with Li were significantly higher than those of rats treated with Dex/Li. Chronic Dex administration resulted in a significant increase in the density (Bmax) of the 5-HT2A receptor without a significant change in the affinity (Kd). The increase in the Bmax induced by Dex was not prevented by chronic combined treatment with Dex and Li. Chronic Dex administration potentiated the WDS, and this increase was prevented by chronic combined treatment with Dex and Li. Chronic Li administration did not have any effect on WDS. These results indicate that chronic Li administration may improve the supersensitivity of the 5-HT2A receptor elicited by chronic Dex administration without decreasing the density of the 5-HT2A receptor, and the effect of Li was also independent of hypothalamo-pituitary-adrenal axis function.

Three sets of diagnostic criteria for major depression and correlations with serotonin-induced platelet calcium mobilization in cancer patients

Abstract. Objective: Enhanced serotonin-induced platelet calcium mobilization has been proposed to be a biological marker for the pathophysiology of major depression in physically healthy patients. To determine the most appropriate method of diagnosing major depression in cancer patients, we compared serotonin-induced platelet calcium mobilization between patients with and without major depression diagnosed according to three different sets of diagnostic criteria (inclusive, substitutive and exclusive). Methods: Among the cancer patients referred to our institution between June 1997 and March 1998, 24 patients diagnosed as having major depression according to the inclusive approach (in which the nine traditional symptoms of major depression contribute towards the diagnosis of depression regardless of its presumed etiology) participated in the study. Serotonin-induced platelet calcium mobilization was examined in these patients and in the same number of non-depressed controls matched for age, sex, cancer stage and cancer site. The depressed patients were then re-evaluated using substitutive and exclusive criteria, and calcium mobilization comparisons with the relevant controls were repeated. Results: Compared with the controls, an enhanced serotonin-induced platelet calcium response was only observed in the patients with major depression according to the exclusive criteria. No significant enhancement was observed when the inclusive or substitutive approaches were used. Conclusion: These findings, based on the use of enhanced serotonin-induced platelet calcium mobilization as a biological marker, suggest that the exclusive approach might be the most valid and appropriate method of diagnosing major depression in cancer patients, while the inclusive and substitutive approaches might overestimate the occurrence of major depression in these patients.

Effect of acute lipopolysaccharide administration on (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane-induced wet dog shake behavior in rats: comparison with body weight change and locomotor activity.

1. Several reports have shown that serotonin (5-HT)2A receptor density and its function are altered after physiological or pharmacological stress. To examine whether an acute administration of lipopolysaccharide (LPS), a bacterial endotoxin, affected 5-HT2A receptor function, wet dog shakes of male Wistar rats were observed after a subcutaneous injection of DOI, a 5-HT2A receptor agonist following LPS treatment. Body weight change and locomotor activity were also observed. 2. DOI (1 mg/kg)-induced WDS significantly decreased after 400 or 1000 microg/kg LPS treatment compared with that of control rats 1 and 3 hr after injection, and WDS completely recovered 8 hr after LPS treatment. Treatment with 10 mg/kg indomethacin (IND) or 1 mg/kg naltrexone (NLTX) canceled the effect of 400 microg/kg LPS on DOI-induced WDS. 3. Body weight decrease was significantly greater in LPS-treated rats compared with control rats 3, 5 and 8 hr after treatment. Treatment with IND (10 mg/kg) significantly recovered the reduction in body weight induced by 400 microg/kg LPS. Treatment with NLTX (1 mg/kg) also prevented the LPS effect on body weight decrease. 4. Eight hr after treatment with LPS (400 microg/kg), the rats showed significant attenuation of locomotor activity. IND (10 mg/kg) treatment abolished the inhibitory effect of LPS on locomotor activity, and NLTX (1 mg/kg) also improved the decrease in locomotion 8 hr after LPS treatment. 5. Plasma tumor necrosis factor (TNF)-alpha concentration dramatically increased 1 hr after the injection of 400 microg/kg LPS, and returned almost to the basal level 3 hr later. Next, rats were injected with 50 microg/kg TNF-alpha intraperitoneally, and body weight change and DOI-induced WDS was determined 3 hr after TNF-alpha injection. Body weight loss was significantly greater in rats treated with TNF-alpha. On the other hand, DOI-induced WDS was not altered when rats were treated with TNF-alpha. 6. These results suggest that acute treatment with LPS inhibited 5-HT2A receptor-mediated behavior via cyclooxygenase and opioid receptor activation, but that the inhibition of the WDS by LPS appears to be independent of TNF-alpha production.

Effect of heat stress on serotonin-2A receptor-mediated intracellular calcium mobilization in rat C6 glioma cells

Summary. This study was conducted to investigate an effect of heat stress at 44°C for 30 min on intracellular Ca2+ signaling system and on heat shock protein (HSP)-70 expression. 5-HT-induced Ca2+ mobilization was reduced 1, 3 and 6 hrs after heat stress, and recovered to the control level 12 and 24 hrs after heat stress. One hr after heat stress, Ca2+ rise was significantly decreased when the cells were stimulated by any concentration of 5-HT. Thrombin-induced Ca2+ increase was also markedly reduced 1 hr after heat stress. HSP-70 level was increased 6 and 9 hr after heat stress. In HSP synthesis inhibitor quercetin-treated cells, HSP-70 expression was not enhanced after heat stress, and Ca2+ rise in response to 5-HT did not return to the control level. However, the Ca2+ rise induced by 5-HT was not restored to the control level after stress in Ac-Asp-Glu-Val-Asp-H (DEVD)-exposed cells while DEVD had little effect on heat stress-induced synthesis of HSP-70. Dexamethasone did not alter the change in HSP-70 expression or Ca2+ response after heat stress. These results indicate that heat stress attenuated 5-HT-induced Ca2+ mobilization and that HSP-70 expression played an important role in recovery from Ca2+ impairment, possibly via protease activity in C6 cells.

Characterization of 5-HT2A receptor desensitization and the effect of cycloheximide on it in C6 cells.

Summary. Effect of prolonged pretreatment with serotonin (5-HT) on 5-HT2A receptor desensitization was examined by the measurement of intracellular calcium ([Ca2+]i) mobilization in C6 cells. 5-HT-induced desensitization of [Ca2+]i mobilization was in a time and dose dependent manner and reached a plateau after 3 hr. After 1 and 3 hr 5-HT pretreatment, 5-HT concentration in the medium little changed. 5-HT pretreatment with cycloheximide, a protein synthesis inhibitor, produced an enhancement of the desensitization for 3 and 6 hr pretreatment. However, 5-HT pretreatment for 3 and 6 hr caused no marked change in the 5-HT2A receptor mRNA level or Gαq/11 protein in this study, suggesting that 5-HT may decrease 5-HT-induced [Ca2+]i mobilization independent of 5-HT2A receptor mRNA or G-proteins. Endothelin-1-induced [Ca2+]i mobilization did not alter after 5-HT and/or cycloheximide pretreatment. These results showed that activation of the 5-HT2A receptor induced homologous desensitization and pretreatment with 5-HT and/or cycloheximide did not change the efficacy of the second messenger pathway from Gq to a [Ca2+]i rise.

Lack of association between suicidal ideation and enhanced platelet 5-HT2A receptor-mediated calcium mobilization in cancer patients with depression.

BACKGROUNDnIncreased density of 5-HT2A receptors was observed in the platelets of depressive patients with suicidal ideation. Enhanced 5-HT2A receptor-mediated platelet calcium mobilization has been proposed as a biological marker for the pathophysiology of major depression in cancer patients as well as in physically healthy patients. To examine whether depressive cancer patients with suicidal ideation have enhanced 5-HT2A receptor-mediated platelet response compared with those without suicidal ideation, we compared 5-HT-induced platelet calcium mobilization in depressive cancer patients with and without suicidal ideation.nnnMETHODSn5-HT-induced platelet calcium mobilization was examined in 24 cancer patients diagnosed as having major depression according to the DSM-IV criteria. Suicidal ideation was evaluated by the Hamilton Depression Rating Scale and Zungs Self Depression Scale, as well as by the DSM-IV criteria.nnnRESULTSnThere was no significant differences in 5-HT-induced platelet calcium response between the depressive cancer patients with (n = 8) and without suicidal ideation (n = 16). 5-HT-induced platelet calcium response was also not significantly associated with the severity of suicidal ideation or with the severity of depression assessed by Hamilton Depression Rating Scale and Zungs Self Depression Scale.nnnCONCLUSIONSnThese findings suggest that enhanced 5-HT2A receptor-mediated response was not associated with suicidal ideation in cancer patients with depression.

Risperidone treatment of neuroleptic-induced tardive extrapyramidal symptoms

Tardive extrapyramidal symptoms (EPS) induced by neuroleptic treatment, and particularly EPS which persist after withdrawal of the drugs, are clinically serious problems. We describe a patient with four types of tardive and persistent EPS such as dystonia, dyskinesia, choreatic movement and myoclonus, induced by haloperidol. These EPS were remarkably inhibited by 3 mg/day risperidone. This is the first published case demonstrating simultaneous development of these four types of tardive EPS induced by a neuroleptic and then reduced by low-dose risperidone treatment. ( Int J Psych Clin Pract 2000; 4: 241 - 243)