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 b een 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 re sults. To re-examine the antipsychotic potential of CCK-based treatments, w e examined systemic injections of CCK analogs in an animal model with stron g face and construct validity for sensorimotor-gating deficits seen in schi zophrenia patients ann with strong predictive validity for antipsychotic dr ug activity. Prepulse inhibition (PPI) occurs when it weak acoustic lead st imulus ("prepulse") inhibits the startle response to a sudden loud sound (" pulse"). PPI is significantly reduced in schizophrenia patients and rats tr eated with dopamine agonists. Antipsychotics reverse decreased PPI in rats to a degree highly correlated with their clinical efficacy. Subcutaneous (S C) injections of caerulein (10 mu g/kg) a mixed CCKA/B agonist, partially r eversed 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 (devazepid e) but not a CCKB antagonist (L-365,260). CCK-4, a preferential CCKB agonis t, had no significant effect on PPI. These results suggest that caerulein p roduces a weak neuroleptic-like effect PPI that is mediated by stimulation of CCKA receptors. Possible circuities in this effect are discussed. In a s eparate 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 p otential of CCK-based treatments. [Neuropsychopharmacology 20:141-149, 1999 ] (C) 1998 American College of Neuropsychopharmacology. Published by Elsevi er Science Inc.