Enhancement of latent inhibition in the rat by the CCK antagonist proglumide.
The behavioral paradigm of latent inhibition (LI) involves the retardation of conditioning to a stimulus when paired with reinforcement, if preexposure to that stimulus with no significant consequence has occurred. This phenomenon is believed to reflect a process of learning to ignore stimuli as irrelevant. Disruption in LI can be considered to be an attentional deficit observed in schizophrenia. The neuropeptide cholecystokinin (CCK), which coexists with dopamine (DA) in some brain regions, has been implicated in the pathophysiology of schizophrenia. The present study examined the effects of the nonselective CCK antagonist proglumide on LI (0.25, 0.5, and 1.0 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. Administration of 1.0 and 0.5 mg/kg, but not 0.25 mg/kg, proglumide was found to reduce suppression of drinking behavior in animals preexposed (PE) to a flashing light stimulus. These animals developed LI under conditions where preexposed control animals exhibited suppression of drinking behavior similar to that of nonpreexposed (NPE) control animals. These findings for proglumide were comparable to the effects on drinking behavior of 0.1 mg/kg haloperidol. The enhancement of LI by proglumide may be interpreted in terms of CCK dopamine interactions. Because CCK may modulate dopamine, the results reported here for proglumide strengthen the argument for the investigation of CCK-based drugs as potential antipsychotic agents.
Gracey
D J
DJ
Department of Therapeutics and Pharmacology, The Queen's University of Belfast, N. Ireland.
Bell
R
R
King
D J
DJ
Trimble
K M
KM
McDermott
B J
BJ
D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D011377:Proglumide / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D013216:Reflex, Startle / Q000187:drug effects*
D000897:Anti-Ulcer Agents; D014150:Antipsychotic Agents; D011949:Receptors, Cholecystokinin; D017448:Receptors, Dopamine D2; D011377:Proglumide; D006220:Haloperidol