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 modulate 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 and with strong predictive validity for antipsychotic drug activity. Prepulse inhibition (PPI) occurs when a 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 (s.c.) injections of caerulein (10 micrograms/kg) a mixed CCKA/B agonist, partially reversed amphetamine-induced reduction of PPI; whereas, s.c. 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 on PPI that is mediated by stimulation of CCKA receptors. Possible circuities in this effect are discussed. In a separate experiment, s.c. 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.
Feifel
D
D
Department of Psychiatry, University of California, San Diego, La Jolla 92093-8620, USA.
Reza
T
T
Robeck
S
S
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D002108:Ceruletide / Q000627:therapeutic use*; D002766:Cholecystokinin / Q000502:physiology*; D005765:Gastrointestinal Agents / Q000627:therapeutic use*; D006220:Haloperidol / Q000008:administration & dosage / Q000627:therapeutic use; D007279:Injections, Subcutaneous; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011618:Psychotic Disorders / Q000188:drug therapy* / Q000523:psychology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors / Q000187:drug effects; D013216:Reflex, Startle / Q000187:drug effects; D013758:Tetragastrin / Q000037:antagonists & inhibitors / Q000494:pharmacology
D014150:Antipsychotic Agents; D005765:Gastrointestinal Agents; D011949:Receptors, Cholecystokinin; D013758:Tetragastrin; D002108:Ceruletide; D002766:Cholecystokinin; D006220:Haloperidol