Low-dose clozapine but not haloperidol attenuates ketamine-induced deficits under an incremental repeated acquisition procedure

Abstract

Ketamine, like other N-methyl-D-aspartate (NMDA) receptor antagonists, causes both locomotor and cognitive dysfunction, decrements that may be mediated by distinct neurotransmitter systems. The present study was designed to characterize the contributions of dopamine and serotonin to the behavioral effects of ketamine. BALB/c mice responding under an incremental repeated acquisition procedure were administered ketamine alone and in combination with haloperidol pretreatment or clozapine pretreatment. Ketamine (1-30 mg/kg) dose-dependently decreased response rate, reinforcer rate, maximum chain length, and progress quotient (a weighted measure of overall performance). The Performance chain was more sensitive to ketamine’s effect than were the Learning chains. Pretreatment with clozapine (0.1-4.0 mg/kg) dose-dependently attenuated disruption of IRA responding by systemic ketamine (30 mg/kg). No dose of haloperidol pretreatment (0.01-0.1 mg/kg) alleviated ketamine-induced IRA deficits (30 mg/kg). The effectiveness of clozapine relative to haloperidol suggests a more central role of specific serotonergic receptors over dopaminergic receptors in mediating the behavioral effects of ketamine.