PD-135,158, a cholecystokinin(B) antagonist, enhances latent inhibition inthe rat

The antipsychotic potential of cholecystokinin (CCK)-related compounds stem s from CCK's colocalization with dopamine (DA). CCK demonstrates excitatory and inhibitory effects on DA in the mesolimbic pathway. Such diverse actio ns might be mediated by different receptor subtypes (CCKA or CCKB). Multipl e hypotheses have emerged regarding the clinical application of CCK-based d rugs. Administering selective nonpeptide antagonists within animal models r elevant to schizophrenia would help delineate CCK receptor involvement. One animal model simulating a cognitive dysfunction of schizophrenia is latent inhibition (LI). An animal repeatedly exposed to a stimulus that is devoid of consequence is subsequently inhibited in making new associations with t hat stimulus. This reflects a process of learning to ignore irrelevant stim uli. The present study examined the effects of the selective CCKB antagonis t PD-135,158 (0.001, 0.01, and 0.1 mg/kg) using a conditioned suppression o f drinking procedure in rats. For purposes of comparison the effects of hal operidol (0.1 mg/kg) were also investigated. PD-135,158 (0.1 mg/kg), simila r to haloperidol (0.1 mg/kg), elicited a clear LI effect under conditions t hat did not lead to LI in control rats (low number of preexposures). These findings highlight the antipsychotic potential of CCKB antagonists, and fur ther illustrate the LI paradigm's capacity to detect novel, antipsychotic-l ike, drug activity. (C) 2000 Elsevier Science Inc.