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

The antipsychotic potential of cholecystokinin (CCK)-related compounds stems from CCK's colocalization with dopamine (DA). CCK demonstrates excitatory and inhibitory effects on DA in the mesolimbic pathway. Such diverse actions might be mediated by different receptor subtypes (CCK(A) or CCK(B)). Multiple hypotheses have emerged regarding the clinical application of CCK-based drugs. Administering selective nonpeptide antagonists within animal models relevant 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 that stimulus. This reflects a process of learning to ignore irrelevant stimuli. The present study examined the effects of the selective CCK(B) antagonist PD-135,158 (0.001, 0. 01, and 0.1 mg/kg) using a conditioned suppression of drinking procedure in rats. For purposes of comparison the effects of haloperidol (0.1 mg/kg) were also investigated. PD-135,158 (0.1 mg/kg), similar to haloperidol (0.1 mg/kg), elicited a clear LI effect under conditions that did not lead to LI in control rats (low number of preexposures). These findings highlight the antipsychotic potential of CCK(B) antagonists, and further illustrate the LI paradigm's capacity to detect novel, antipsychotic-like, drug activity.