Examination of clozapine and haloperidol in improving ketamine-induced deficits in an incremental repeated acquisition procedure in BALB/c mice.

RATIONALE: Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, causes locomotor hyperactivity, aberrant prepulse inhibition and impaired reversal learning among other deficits. There are numerous clinical and pre-clinically uses of NMDAR antagonists and a growing need to characterize their neurobehavioral effects.

OBJECTIVES: The present study was designed to characterize 1) ketamine's effect on incremental repeated acquisition (IRA), a procedure that taps multiple neurobehavioral functions and has performance measures correlated with IQ in humans, and 2) the extent to which clozapine (CLZ) and haloperidol (HAL) block ketamine's detrimental effects.

METHODS AND RESULTS: In experiment 1 (Exp. 1), BALB/c mice nose-poked under an IRA procedure for sucrose pellets. Systemic ketamine (1-30 mg/kg) dose-dependently decreased measures of cognitive and motor function. CLZ pretreatment (CLZ 0.1-4.0 mg/kg) dose-dependently attenuated ketamine-induced (30 mg/kg) deficits; the effective dose range of CLZ was 0.3-1.0 mg/kg. HAL pretreatment (0.01-0.1 mg/kg) did not attenuate any ketamine-induced deficits. In experiment 2 (Exp. 2), BALB/c mice lever-pressed under an IRA procedure for sweetened condensed milk. Ketamine (30 mg/kg) produced a global impairment in the IRA procedure and CLZ pretreatment (0.3-1.0 mg/kg) dose-dependently attenuated that impairment; motor-based performance recovered to a greater extent than cognitive performance. When tested alone, these doses of CLZ had little effect on IRA performance.

CONCLUSIONS: These findings support the notion that CLZ is more effective than HAL at blocking ketamine-induced deficits. The IRA procedure may be beneficial for distinguishing the efficacy of drugs that seek to alleviate deficits in complex behavior that result from acute NMDAR antagonism.