Haloperidol- and clozapine-induced enhancement of latent inhibition with extended conditioning: implications for the mechanism of action of neuroleptic drugs

Abstract

Latent inhibition (LI) refers to retarded conditioning to a stimulus as a consequence of its nonreinforced preexposure. LI is impaired in acute schizophrenic patients and in rats treated with amphetamine. Neuroleptic drugs enhance LI, and this effect is selective and specific for this class of drugs. The present experiments tested the proposition that neuroleptic-induced enhancement of LI stems from decreased capacity of stimulus-preexposed animals to switch responding according to the new stimulus-reinforcement contingency in the conditioning stage. LI was assessed using an off-baseline conditioned emotional response (CER) procedure in rats licking for water, consisting of three stages: preexposure to the-to-be conditioned stimulus, tone; conditioning, in which the preexposed stimulus was paired with a foot-shock; and test, in which LI was indexed by animals' degree of suppression of licking during tone presentation. Whereas in previous studies that demonstrated LI enhancement by neuroleptics, preexposure consisted of 10 to 40 tones, and conditioning included two tone-shock pairings, the present experiments used 40 tone preexposures, followed by an extended conditioning stage with five tone-shock pairings. It was expected that under these conditions no LI effect would be evident in untreated animals, but that animals treated with a neuroleptic drug, either during the entire LI procedure or only in conditioning, would show LI. Experiments 1 and 2 showed that LI was obtained in rats treated with haloperidol (0.1 mg/kg in experiment 1, 0.03 and 0.2 mg/kg in experiment 2) but not in the untreated controls. Experiment 3 showed that the same outcome was obtained when haloperidol (0.1 mg/kg) administration was confined to the conditioning stage. Experiment 4 showed that clozapine (5 mg/kg)-treated animals showed LI when the drug was confined to conditioning, but not to the preexposure stage. The implications of these results for the mechanism of action of neuroleptic drugs are discussed.