Shoko Hirano

Diabetes Attenuates the Antidepressant-Like Effect Mediated by the Activation of 5-HT1A Receptor in the Mouse Tail Suspension Test

Several lines of evidence have indicated that the prevalence of depression in diabetic subjects is higher than that in the general population, however, little information is available on the effects of antidepressants in diabetes. In the present study, the antidepressant-like effect mediated by the activation of 5-HT1A receptors was examined using the tail suspension test in streptozotocin-induced diabetic mice. Long-lasting increases in 5-HT turnover rates were observed in the diabetic mouse midbrain and frontal cortex, but not in the hippocampus. Duration of immobility was significantly longer in diabetic than in nondiabetic mice in the tail suspension test. The 5-HT1A receptor agonist (±)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (3–30 μg/kg, i.p.) reduced the duration of immobility in nondiabetic mice, and this effect was completely antagonized by pretreatment with N-[2-[4-(2-methoxyphenil)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY-100635) (30 μg/kg, s.c.), a selective 5-HT1A receptor antagonist. In contrast, 8-OH-DPAT (3 μg/kg–3 mg/kg, i.p.) was ineffective in diabetic mice. The selective 5-HT reuptake inhibitor fluoxetine (3–56 mg/kg, i.p.) reduced the duration of immobility in both nondiabetic and diabetic mice. However, fluoxetine was less effective in diabetic mice than in nondiabetic mice. WAY-100635 (30 μg/kg, s.c.) reversed the suppression of the duration of immobility by fluoxetine (30 mg/kg, i.p.) in nondiabetic mice. On the other hand, the anti-immobility effect of fluoxetine (56 mg/kg, i.p.) was not antagonized by WAY-100635 (30 μg/kg, s.c.) in diabetic mice. The selective 5-HT2 receptor antagonist 6-methyl-1-(1-methylethyl)-ergoline-8β-carboxylic acid 2-hydroxy-1-methylpropyl ester (LY53,857) (30 μg/kg, s.c.) reversed the anti-immobility effect of fluoxetine in both nondiabetic and diabetic mice. Spontaneous locomotor activity in diabetic mice was not different from that in nondiabetic mice. 8-OH-DPAT (30 μg/kg, i.p.), but not fluoxetine, increased the spontaneous locomotor activity in both nondiabetic and diabetic mice. The number of 5-HT1A receptors in the mouse frontal cortex was unaffected by diabetes. Plasma corticosterone levels in diabetic mice were significantly higher than that in nondiabetic mice. These results suggest that the antidepressant-like effect mediated by 5-HT1A receptors may be attenuated by diabetes.

Diabetes attenuates psychological stress-elicited 5-HT secretion in the prefrontal cortex but not in the amygdala of mice

It is well established that diabetes widely affects the functioning of the central nervous system. However, no in vivo study assessed the serotonin (5-HT)-releasing system in the prefrontal cortex (PFC) and amygdala--the crucial regions regulating emotion. We investigated the effects of streptozotocin (STZ)-induced diabetes on the levels of extracellular 5-HT in the PFC and amygdala by using an in vivo microdialysis technique in mice. In addition, the effects of psychological stress on 5-HT secretion were also examined. The basal and the selective 5-HT reuptake inhibitor citalopram (1 microM)-accumulated 5-HT levels remained unchanged in both the PFC and amygdala of diabetic mice. The elevated open platform stress-elicited 5-HT secretion was significantly decreased in the PFC of diabetic mice, and this blunted response was normalized by sub-chronic pretreatment with insulin (5 U/kg, s.c., twice daily). Diabetes had no significant effect on the KCl (100 mM)-stimulated 5-HT release in the PFC. In the amygdala, diabetes had no effect on the stress-elicited 5-HT secretion. Diabetic mice exhibited prolonged freezing as compared to the non-diabetic mice in the elevated open-platform test. In addition, insulin-treated diabetic mice showed the significant shorter duration of freezing than that in diabetic mice. In conclusion, our present findings indicate that diabetes attenuates the serotonergic response to stressful stimuli in a site-specific fashion. In addition, we suggest the possibility that the dysfunction of stress-elicited 5-HT release, but not basal 5-HT release, causes the increased expression of fear-related behavior in diabetic mice.

Antidepressant-like effect of leptin in streptozotocin-induced diabetic mice

We previously reported that streptozotocin (STZ)-induced diabetic mice showed the depressive-like behavior in the tail suspension test. It has also been reported that leptin-deficient obese mice demonstrate the depressive-like behavior. Since STZ-induced diabetes causes a marked decrease in plasma leptin levels, it is possible that decrease in leptin levels and the depressive-like behavior may somehow be related. Therefore, we examined the effect of leptin on the depressive-like behavior of STZ-induced diabetic mice in the tail suspension test. The prolonged duration of immobility in diabetic mice was dose-dependently and significantly suppressed by single treatment with leptin (0.1-1 mg/kg, i.p.) without affecting on the locomotor activity. Leptin did not affect either the duration of immobility or the locomotor activity in non-diabetic mice. The anti-immobility effect of leptin (1 mg/kg, i.p.) in diabetic mice was significantly antagonized by the selective serotonin2 (5-HT2) receptor antagonist LY53,857 (0.03 mg/kg, s.c.), but not by the selective 5-HT1A receptor antagonist WAY-100635 (0.03 mg/kg, s.c.). Antagonists administered alone did not affect either the duration of immobility or the locomotor activity in diabetic mice. In conclusion, we suggest that leptin exerts the antidepressant-like effect in diabetic mice mediated by, at least in part, 5-HT2 receptors.

Effects of histamine H1 receptor antagonists on depressive-like behavior in diabetic mice

We previously reported that streptozotocin-induced diabetic mice showed depressive-like behavior in the tail suspension test. It is well known that the central histaminergic system regulates many physiological functions including emotional behaviors. In this study, we examined the role of the central histaminergic system in the diabetes-induced depressive-like behavior in the mouse tail suspension test. The histamine contents in the hypothalamus were significantly higher in diabetic mice than in non-diabetic mice. The histamine H(1) receptor antagonist chlorpheniramine (1-10 mg/kg, s.c.) dose-dependently and significantly reduced the duration of immobility in both non-diabetic and diabetic mice. In contrast, the selective histamine H(1) receptor antagonists epinastine (0.03-0.3 microg/mouse, i.c.v.) and cetirizine (0.01-0.1 microg/mouse, i.c.v.) dose-dependently and significantly suppressed the duration of immobility in diabetic mice, but not in non-diabetic mice. Spontaneous locomotor activity was not affected by histamine H(1) receptor antagonists in either non-diabetic or diabetic mice. In addition, the number and affinity of histamine H(1) receptors in the frontal cortex were not affected by diabetes. In conclusion, we suggest that the altered neuronal system mediated by the activation of histamine H(1) receptors is involved, at least in part, in the depressive-like behavior seen in diabetic mice.

Abnormal benzodiazepine receptor function in the depressive-like behavior of diabetic mice

We previously reported that streptozotocin (STZ)-induced diabetic mice exhibited depressive-like behavior in the tail suspension test. In this study, we examined the involvement of benzodiazepine receptor functions in this diabetes-induced depressive-like behavior in mice. STZ-induced diabetes significantly increased the duration of immobility without affecting spontaneous locomotor activity. This increase was dose-dependently and significantly suppressed by a benzodiazepine receptor antagonist, flumazenil (0.1-1 mg/kg, i.v.). However, flumazenil (0.1-1 mg/kg, i.v.) did not affect the duration of immobility in non-diabetic mice. Furthermore, flumazenil (1 mg/kg, i.v.) had no significant effect on spontaneous locomotor activity in either non-diabetic or diabetic mice. The benzodiazepine receptor inverse agonist methyl beta-carboline-3-carboxylate (beta-CCM; 0.03-0.3 mg/kg, i.v.) dose-dependently and significantly increased the duration of immobility in non-diabetic mice, but not in diabetic mice. beta-CCM (0.3 mg/kg, i.v.) significantly suppressed spontaneous locomotor activity in non-diabetic mice, but not in diabetic mice. These results indicate that diabetic mice may have enhanced negative allosteric modulation by benzodiazepine receptor ligands, such as diazepam binding inhibitors, under stressful conditions, but not free-moving conditions, and this abnormal function of benzodiazepine receptors may cause, at least in part, the expression of depressive-like behavior in diabetic mice.