HALOPERIDOL-INDUCED AND CLOZAPINE-INDUCED ENHANCEMENT OF LATENT INHIBITION WITH EXTENDED CONDITIONING - IMPLICATIONS FOR THE MECHANISM OF ACTION OF NEUROLEPTIC DRUGS

Latent inhibition (LI) refers to retarded conditioning to a stimulus a s a consequence of its nonreinforced preexposure. LI is impaired in ac ute schizophrenic patients and in rats treated with amphetamine. Neuro leptic drugs enhance LI, and this effect is selective and specific for this class of drugs. The present experiments tested the proposition t hat neuroleptic-induced enhancement of LI stems from decreased capacit y 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: pre exposure to the-to-be conditioned stimulus was paired with a foot-shoc k; 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, th e present experiments used 40 tone preexposures, followed by an extend ed conditioning stage with five tone-shock pairings. It was expected t hat under these conditions no LI effect would be evident in untreated animals, but that animals treated with a neuroleptic drug, either duri ng the entire LI procedure or only in conditioning, would show LI. Exp eriments 1 and 2 showed that LI was obtained in mts treated with halop eridol (0.1 mg/kg in experiment 1, 0.03 and 0.2 mg/kg in experiment 2) but nor in the untreated controls. Experiment 3 showed that the same outcome was obtained when haloperidol (0.1 mg/kg) administration was c onfirmed to the conditioning stage. Experiment 4 showed that clozapine (5 mg/kg)-treated animals showed LI when the drug was confined to con ditioning, but not to the preexposure stage. The implications of these results for the mechanism of action of neuroleptic drugs are discusse d. (C) 1997 American College of Neuropsychopharmacology.