Toluene inhalation is a common form of substance abuse. Chronic toluene use can cause persistent psychiatric symptoms even after cessation of toluene use. Our previous studies have shown that adolescent toluene exposure causes cognitive impairment and social dysfunction in mice, which can be reversed by atypical antipsychotics, such as clozapine and aripiprazole. This investigation was designed to extend the previous findings and identify the role of 5-HT_1A receptors in the beneficial effects of atypical antipsychotics. Male NMRI mice received injection per day of either toluene (750 mg/kg) or oil at postnatal day P35-P39, and P42-P46. Behavioral tests were conducted after 7-day washout period to confirm the toluene-treated animals with long-lasting behavioral impairment. Thereafter, toluene-treated mice were administered with the antipsychotics clozapine (20 mg/kg), aripiprazole ( 0.1 and 0.3 mg/kg) or buspirone (1 and 5 mg/kg), a 5-HT_1A receptor partial agonist, alone or co-administered with WAY100635 (0.5 mg/kg), a serotonin 5-HT_1A receptor antagonist, 1 hr prior to behavioral tests. The results showed that acute treatment of clozapine, aripiprazole and buspirone could effectively ameliorate the toluene-induced social and cognitive impairment and these effects were blocked by co-treatment with WAY100635. Our findings suggest that an interaction with 5-HT_1A receptors might be at least in part, responsible for the beneficial effects of clozapine and aripiprazole on toluene-induced social and cognitive deficits and 5-HT_1A receptor agonists might be novel therapeutic agents for treatment of behavioral disorders related to toluene abuse.