Rosiglitazone treatment reversed depression- but not psychosis-like behavior of db/db diabetic mice

Abstract

The objective of the present study was to examine the effect of long-term management of insulin resistance and hyperglycemia on neurobehavioral deficits in db/db mice. In this study, 5-week-old db/db and lean control mice were fed with rosiglitazone (20 mg/kg/day) mixed or standard chow for a duration of 5 weeks. Mice were monitored weekly for blood glucose concentration. Five weeks after the onset of treatment, they were subjected to the forced swim test (FST), pre-pulse inhibition (PPI), open field test (OFT) and fear-potentiated startle (FPS) test to examine for depression, psychosis-like behavior, locomotor activity and emotional learning, respectively. Rosiglitazone normalized hyperglycemia and improved glucose tolerance. Rosiglitazone significantly reduced immobility time in the FST in db/db mice, suggesting an antidepressant-like effect. However, rosiglitazone failed to reverse disruption of PPI in db/db mice, indicating its ineffectiveness against psychosis-like behavior. In the OFT, rosiglitazone did not affect the activity of db/db mice, suggesting its antidepressant-like effect was independent of changes in locomotor activity. In the FPS test, db/db mice showed impaired emotional learning and rosiglitazone failed to correct it. In conclusion, long-term blood glucose management in type-2 diabetics may help to limit the co-occurrence of depression but not the psychotic symptoms and ability to cope with stress.

Dicholine succinate, the neuronal insulin sensitizer, normalizes behavior, REM sleep, hippocampal pGSK3 beta and mRNAs of NMDA receptor subunits in mouse models of depression

“…For instance, rosiglitazone, one of the insulin sensitizers of the thiazolidinedione class, induces an antidepressant-like effect in the tail suspension and forced swim tests in mice, reducing immobilization and floating behavior (Eissa Ahmed and Al-Rasheed, 2009). Similar effects were found for pioglitazone, another insulin receptor sensitizer, which were shown to be NMDA receptor-dependent (Salehi-Sadaghiani et al, 2012; Sharma et al, 2012). Rosiglitazone and pioglitazone were reported to be effective in the treatment of major depressive disorder that was refractory to standard antidepressant treatment and accompanied by insulin resistance (Rasgon et al, 2010; Kemp et al, 2011).…”

Insulin resistance in brain alters dopamine turnover and causes behavioral disorders

“…Importantly, this depressive phenotype can be reversed by treatment with antidepressive drugs. Previous studies have shown that treating obese, diabetic mice with the insulin sensitizer rosiglitazone, which has been shown to reduce reactive oxygen species formation in the brain (59), can also decrease depressive-like behavior (60). Whether this decrease is through increasing insulin sensitivity in the brain or systemically remains to be determined.…”

Hippocampal GSK3β as a Molecular Link Between Obesity and Depression

“…For instance, streptozotocin-treated or db/db diabetic mice exhibit lengthened immobility in the FST, which can be partially reversed by insulin [41]. In addition, rosiglitazone, an anti-diabetic compound improving insulin sensitivity by up-regulation of PI3K/Akt pathway [42], exhibits antidepressant properties in control and diabetic (db/db) mice [43]. However, an alteration of locomotor activity has been observed in these models, limiting the interpretation of the results.…”