Beneficial effects of atypical antipsychotics on object recognition deficits after adolescent toluene exposure in mice: involvement of 5-HT_1A receptors

ABSTRACT

Background: Inhalant (e.g. toluene) misuse by adolescents has been linked to psychosis and persistent cognitive deficits. Identifying effective strategies to improve cognitive deficits following chronic toluene misuse is critical. 5-HT_1A receptor has been proposed as a target for the treatment of cognitive deficits.

Objectives: We compared the effects of antipsychotics on recognition deficits after adolescent toluene exposure in mice and elucidated the role of 5-HT_1A receptors in the cognition-improving effects of antipsychotics.

Methods: Male NMRI mice (n = 279) received one injection per day of either toluene (750 mg/kg) or corn oil at postnatal days 35–39 and 42–46. Thereafter, the acute and subchronic effects of haloperidol, aripiprazole, or clozapine on toluene-induced recognition deficits were evaluated by novel object recognition test.

Results: Acute administration of aripiprazole (p < .05) and clozapine (p < .01), but not haloperidol, significantly attenuated the toluene-induced recognition deficits. Pretreatment with 5-HT_1A receptor antagonist WAY -100,635 (p < .05) blocked their beneficial effects. Moreover, 5-HT_1A receptor agonist buspirone (p < .01) ameliorated the toluene-induced recognition deficits, which was reversed by WAY -100,635 (p < .001). Finally, after repeated treatment with clozapine, aripiprazole, and buspirone daily for 14 days, the impaired object recognition in toluene-exposed mice was significantly improved (p < .05) and the beneficial effects lasted for at least 2 weeks (p < .05).

Conclusions: The results indicate that clozapine and aripiprazole, which display 5-HT_1A agonist properties, restored cognitive deficits in mice induced by adolescent toluene exposure. These findings suggest that these antipsychotics should be further explored as a potential treatment option for cognitive deficits in patients with psychosis associated with toluene exposure.

KEYWORDS:

• Toluene
• haloperidol
• clozapine
• aripiprazole
• buspirone
• recognition

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author’s contributors

MYL conducted the experiments. CPH assisted with data analysis and wrote the first draft of the manuscript with MYL. MHC and HHC provided the study concept and critical revision of the manuscript.

Additional information

Funding

This work was supported by the Ministry of Science and Technology under Grant [NSC 99-2314-B-400-005-MY3] and National Health Research Institutes under Grant [NP-103-PP-02]; Ministry of Science and Technology, Taiwan [NSC 99-2314-B-400-005-MY3]; National Health Research Institutes, Taiwan [NP-103-PP-02].