Antipsychotic potential of CCK-based treatments: An assessment using the prepulse inhibition model of psychosis

Systemic injections of cholecystokinin (CCK), a "gut-brain" peptide, have been shown to moderate brain dopamine function and produce neuroleptic-like effects on such dopamine-regulated behaviors as locomotor activity. However, clinical trials of CCK agonists in schizophrenia patients showed mixed results. To re-examine the antipsychotic potential of CCK-based treatments, we examined systemic injections of CCK analogs in an animal model with strong face and construct validity for sensorimotor-gating deficits seen in schizophrenia patients ann with strong predictive validity for antipsychotic drug activity. Prepulse inhibition (PPI) occurs when it weak acoustic lead stimulus ("prepulse") inhibits the startle response to a sudden loud sound ("pulse"). PPI is significantly reduced in schizophrenia patients and rats treated with dopamine agonists. Antipsychotics reverse decreased PPI in rats to a degree highly correlated with their clinical efficacy. Subcutaneous (SC) injections of caerulein (10 mu g/kg) a mixed CCKA/B agonist, partially reversed amphetamine-induced reduction of PPI; whereas, SC haloperidol (0.5 mg/kg) totally reversed amphetamine-induced disruption of PPI. Caerulein's effect on PPI was blocked by pretreatment with a CCKA antagonist (devazepide) but not a CCKB antagonist (L-365,260). CCK-4, a preferential CCKB agonist, had no significant effect on PPI. These results suggest that caerulein produces a weak neuroleptic-like effect PPI that is mediated by stimulation of CCKA receptors. Possible circuities in this effect are discussed. In a separate experiment, SC caerulein produced to a more potent neuroleptic-like profile on amphetamine-induced hyperlocomotion, suggesting that selection of preclinical paradigms may be important in evaluating the antipsychotic potential of CCK-based treatments. [Neuropsychopharmacology 20:141-149, 1999] (C) 1998 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.