Rivastigmine improves hippocampal neurogenesis and depression-like behaviors via 5-HT1A receptor stimulation in olfactory bulbectomized mice

• Rivastigmine ameliorates depressive-like behaviors in olfactory bulbectomized mice.
• 5-HT1A receptor is involved in rivastigmine-induced anti-depressive effects.
• Rivastigmine-induced neurogenesis is partially mediated by 5-HT1A receptor.

Rivastigmine is a non-competitive inhibitor of both acetylcholinesterase (AChE) and butylcholinesterase (BuChE) used to treat mild to moderate dementia in Alzheimer’s disease (AD) patients. Although rivastigmine reportedly ameliorates cognitive dysfunction in these patients, its ability to improve Behavioral and Psychological Symptoms of Dementia (BPSD) remains unclear. To determine whether rivastigmine treatment antagonizes depression-like behaviors, we chronically administered rivastigmine (0.1–1.0 mg/kg) to olfactory bulbectomized (OBX) mice once a day for 2 weeks, starting 2 weeks after bulbectomy. Chronic treatment at 0.3 or 1.0 mg/kg dose dependently and significantly improved depression-like behaviors, as assessed by tail suspension (TST), forced swim (FST), locomotion and novelty-suppressed feeding (NSFT) tests. Importantly, co-administration with WAY-100635 (1.0 mg/kg), a 5-HT1A receptor antagonist, but not ketanserin (1.0 mg/kg,), a 5-HT2A receptor antagonist, completely blocked rivastigmine-induced anti-depressive effects, suggesting that 5-HT1A receptor stimulation mediates this activity. Consistent with this observation, rivastigmine treatment significantly rescued impaired neurogenesis observed in OBX mice in a 5-HT1A receptor-dependent manner. Furthermore, enhanced protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) phosphorylation seen following rivastigmine treatment was closely associated with improved neurogenesis. These effects were blocked by WAY-100635 but not ketanserin treatment. Finally, we confirmed that 5-HT1A but not 5-HT2A receptor stimulation by specific agonists mimicked rivastigmine-induced anti-depression activity and promoted hippocampal neurogenesis. We conclude that, in addition to enhancing the cholinergic system, rivastigmine treatment restores normal function of the hippocampal serotonergic system, an activity that likely ameliorates depressive behaviors in AD patients.