Acetamiprid (ACE), is a popular neonicotinoid pesticide, that has a high affinity for mammalian nicotinic acetylcholine receptors (nAChRs). Therefore, ACE might induce depressive effects by perturbing the cholinergic system in mammalian. The aim of this study was to evaluate the effects of ACE exposure on depressive-like behaviors and grip strength (GS) in mice. Also the possible role of nAChR activation in depression was assessed by varenicline, and bupropion. Male Swiss mice (27 ± 2 g) were daily exposed to ACE by gavage (0.1, 1, 5 mg/kg), behavioral tests took place after 3 h, 7 days and 15 days, the subacute ACE (0.1 mg/kg) exposure was assessed after 30 days. Varenicline (0.5 mg/kg) or bupropion (4 mg/kg) were injected intraperitoneally 30 min prior exposure to (1 mg/kg) ACE. The locomotor activity, forced swimming test (FST), and sucrose preference (SP) test were assessed. After a week ACE dose dependently increased the immobility time during FST, and after 15 days' depressive behavior was observed equally for ACE (0.1-5 mg/kg). The subacute exposure (0.1 mg/kg) significantly increased the immobility time, SP also declined that revealed anhedonia. These behavioral changes showed that ACE can initiate depressive effects. The changes in locomotor activity were not significant. GS significantly reduced following a week of exposure to ACE (1-5 mg/kg) that indicated neurotoxicity. These effects were antagonized by bupropion or varenicline, thus ACE effect on nAChRs was essential in initiating the depressive behavior.