Thioperamide

The role of central histamine in diabetes induced behavioral despair is still an enigma. Therefore, the current research explored the plausible impact of the central histaminergic activity on the expression of diabetes-induced behavioral despair in mice using the tail suspension test (TST) and surose preference test (SPT) along with changes in the levels of BDNF and phosphorylated CREB (pCREB) in the whole brain, hippocampus, PFC, and amygdala. Post-streptozotocin (STZ) (200 mg/kg, i.p.) injection, on the 4^th day (called diabetic zero day), rendered the mice diabetic, while the highest blood glucose levels were observed on the 10^th day (behavioral expression and biochemical testing day) post diabetes induction. Furthermore, on the 10^th day, the diabetic mouse elicits a prolonged period of immobility on TST and reduced percentage of sucrose preference on SPT with decreased locomotion, indicating the expression of diabetes induced behavioral despair. Moreover, on the 10^th day, i.c.v. injection of histaminergic agents like histamine, its precursor, L-histidine, neuronal releaser of histamine (H₃ receptor antagonist), thioperamide, the H₁ receptor agonist, FMPH, or the H₂ receptor agonist, amthamine reversed the expression of diabetes induced behavioral despair in mice on TST. In addition, the TST effective doses of (i.c.v.) histamine (50 μg), L-histidine (2.5 μg), thioperamide (10 μg) and FMPH (6.5 μg) also restored the the sucrose consumption reduced in diabetic mice on SPT. Moreover, the ELISA test revealed that in the behaviorally depressed diabetic mice, the whole brain histamine levels were substantially diminished compared to the non-diabetic control mice. In addition, BDNF/pCREB levels was also considerably reduced in the whole brain, hippocampus, PFC, and amygdala of diabetic mice. Conversely, i.c.v. injection of histamine to diabetic mice restored the diminished BDNF/pCREB levels in the whole brain and hippocampus, while thioperamide normalized these deficits in the whole brain, hippocampus, and PFC. However, L-histidine treatment failed to alter reduced BDNF/pCREB levels in all brain regions of diabetic mice. Moreover, i.c.v. injection of FMPH to diabetic mice also reversed the deficit in BDNF/pCREB levels in the whole brain and hippocampus, whereas amthamine injection normalized these markers in the whole brain only. Thus, the enhanced central histaminergic transmission via H₁/H₂ receptors activation might attenuate the diabetes induced behavioral despair in mice by restoring BDNF/pCREB levels in the brain regions implicated in behavioral depression.