Distinct neural mechanisms underlying acute and repeated administration of antipsychotic drugs in rat avoidance conditioning

Rationale: Acute antipsychotic treatment disrupts conditioned avoidance responding, and repeated treatment induces a sensitization- or tolerance-like effect. However, the neurochemical mechanisms underlying both acute and repeated antipsychotic effects remain to be determined. Objective: The present study examined the neuroreceptor mechanisms of haloperidol, clozapine, and olanzapine effect in a rat two-way conditioned avoidance model. Methods: Well-trained Sprague-Dawley rats were administered with haloperidol (0.05 mg/kg, sc), clozapine (10.0 mg/kg, sc), or olanzapine (1.0 mg/kg, sc) together with either saline, quinpirole (a selective dopamine D_2/3 agonist, 1.0 mg/kg, sc), or 2,5-dimethoxy-4-iodo-amphetamine (DOI; a selective 5-HT_2A/2C agonist, 2.5 mg/kg, sc), and their conditioned avoidance responses were tested over 3 days. After 2 days of drug-free retraining, the repeated treatment effect was assessed in a challenge test. Results: Pretreatment of quinpirole, but not DOI, attenuated the acute haloperidol-induced disruption of avoidance responding and to a lesser extent, olanzapine-induced disruption. In contrast, pretreatment of DOI, but not quinpirole, attenuated the acute effect of clozapine. On the repeated effect, pretreatment of DOI, but not quinpirole, attenuated the potentiated disruption of haloperidol, whereas pretreatment of quinpirole attenuated the potentiated disruption of olanzapine but enhanced the tolerance-like effect of clozapine. Conclusions: These findings suggest that acute haloperidol and olanzapine disrupt avoidance responding primarily by blocking dopamine D₂ receptors, whereas acute clozapine exerts its disruptive effect primarily by blocking the 5-HT_2A receptors. The repeated haloperidol effect may be mediated by 5-HT_2A/2C blockade-initiated neural processes, whereas the repeated clozapine and olanzapine effect may be mediated by D_2/3 blockade-initiated neural processes.