Abstract
Neuroleptic-free schizophrenic patients received caerulein, a potent analogue of cholecystokinin octapeptide, in a fixed- and rising-dose schedule. In addition, neuroleptic-treated patients received a single dose of the peptide with a 4-week follow-up. No significant change in mental status was observed after any of these administration schedules. Peak plasma levels of caerulein were noted at 20–30 min after IM administration; at this time no changes in cortical evoked potential were demonstrated. Furthermore, levels of cholecystokinin were not found to be reduced, but were in fact elevated in lumbar cerebrospinal fluid of schizophrenic patients. These data argue against the antipsychotic efficacy of systemic caerulein administration and, because evidence of CNS response to CCK is lacking, suggest that other pharmacologic strategies may be necessary to effectively modify central peptide systems with systemically administered drugs.
Similar content being viewed by others
References
Beinfeld MD, Meyer DK, Eskay RL, Jensen RT, Browstein MJ (1981) The distribution of cholecystokinin immunoreactivity in the central nervous system of the rat as determined by radioimmunoassay. Brain Res 212:51–57
Bruno G, Ruggieri S, Chase TN, Bukker K, Tamminga CA (1985) Caerulein treatment of Parkinson's disease. Clinical Neuropharm (in press)
Chase TN, Barone P, Bruno G, Cohen SL, Juncos J, Knight M, Ruggeri S, Steardo L, Tamminga CA (1985) Cholecystokinin mediated synaptic function and the treatment of neuropsychiatric disease. Neuronal cholecystokinin, New York Academy of Science (in press)
Cohen SL, Knight M, Tamminga CA, Chase TN (1983) Tolerance to the anti-avoidance properties of cholecystokinin-octapeptide. Peptides 4:67–70
Cohen SL, Knight M, Tamminga CA, Chase TN (1985) A comparison of peripheral and central effects of CCK8 on water-reinforced operant responding. Eur J Pharmacol (in press)
Dockray GL (1976) Immunochemical evidence of cholecystokinin-like peptides in brain. Nature 264:568–570
Ferrier IN, Roberts GW, Crow TJ, Johnstone EC, Owens DGC, Lee YC, O'Shaughnessy D, Adrain TE, Polak JM, Bloom SR (1983) Reduced cholecystokin-like and somatostatin-like immunoreactivity in limbic lobe is associated with negative symptoms in schizophrenia. Life Sci 33:475–482
Fuxe K, Andersson V, Locutelli V, Agnati LF, Hokfelt T, Skirboll L, Mutt V (1980) Cholecystokinin peptides produce marked reduction of dopamine turnover in discrete areas in the rat brain following intraventricular injection. Eur J Pharmacol 67:329–331
Gerner RH, Yamada T (1982) Altered neuropeptide concentrations in cerebrospinal fluid of psychiatric patients. Brain Res 238:298–302
Haier RJ (1984) Acute neuroleptic effects on the cortex of schizophrenics: Evoked potential mapping and clinical response. Presented at Amer Psychopath Assn, and Soc Biol Psychiat
Hedlund JL, Vieweg BW (1980) The brief psychiatric rating scale (BPRS): A comprehensive review. J Op Psychiatr 11:48–65
Hokfelt T, Rehfeld L, Skirboll B, Ivemark M, Goldstein M, Markey K (1980) Evidence for coexistence of dopamine and CCK in meso-limbic neurons. Nature 285:476–478
Hommer DW, Pickar D, Roy A, Ninan P, Boronow J, Paul SM (1984) The effects of Ceruletide in Schizophrenia. Arch Gen Psychiatry 41:617–622
Ishibashi S, Oomura Y, Okajima T, Shibata S (1979) Cholecystokinin, motilin and secretin effects on the central nervous system. Physiol Behav 23:401–403
Lotstra F, Verbanck P, Mendlewicz J, Vanderhaeghen JJ (1984) No evidence of antipsychotic effect of caerulein in schizophrenic patients free of neuroleptics: a double-blind cross-over study. Biol Psychiatry 6:877–882
Lucignani G, Porrino LJ, Tamminga CA (1984) Effects of systemically administered cholecystokinin-octapeptide on local cerebral catabolism. Eur J Pharmacol 101:147–151
Markstein R, Hokfelt T (1984) Effect of cholecystokinin-octapeptide on dopamine release from slices of cat caudate nucleus. J Neurosci 4:570–575
Mattes JA, Hom W, Rochford JM, Orlosky M (1985) Ceruletide for schizophrenia: A double-blind study. Biol Psychiatry 20:533–538
Moroji T, Watanabe N, Aoki N, Itoh S (1982) Antipsychotic effects of ceruletide (caerulein) on chronic schizophrenia. Arch Gen Psychiatry 39:485–486
Nair NP, Bloom DM, Nestoros JN (1982) Cholecystokinin appears to have antipsychotic properties. Biol Psychiatry 6:509–512
Oldendorf WH (1981) Blood-brain barrier permeability to peptides: pitfalls in measurement. Peptides Suppl 2:109–111
Pinget M, Straus E, Yalow RS (1979) Release of cholecystokinin peptides from a synaptosome-enriched fraction of rat cerebral cortex. Life Sci 25:339–342
Pinget M, Straus E, Yalow RS (1978) Localization of cholecystokinin-like immunoreactivity in isolated nerve terminals. Proc Natl Acad Sci 75:6324–6326
Rehfeld JF, Kruse-Larson C (1978) Gastrin and cholecystokinin in human cerebrospinal fluid. Immunochemical determination of concentrations and molecular heterogeneity Brain Res 155:19–26
Roth WT, Cannon EH (1972) Some features of the auditory evoked response in schizophrenics. Arch Gen Psychiatry 27:466–471
Roth WT, Horvath TB, Pfefferbaum A, Kopell BS (1980) Event related potentials in schizophrenics. Electroencephalogr Clin Neurophysiol 48:127–139
Shagass C, Ornitz EM, Sutton S, Teuting P (1978) Event-related potentials and psychopathology. In: Callaway E, Teuting P, Koslow SH (eds) Event-related brain potentials in man, New York, Academic pp 443–496
Skirboll LR, Grace AA, Hommer DW, Rehfeld J, Goldstein M, Hokfelt T, Bunney BS (1981) Peptide-monoamine coexistence: Studies of actions of cholecystokinin-like peptide on the electrical activity of midbrain dopamine neurons. Neuroscience 6:2111–2124
Steardo L, Knight M, Tamminga CA, Chase TN (1985) Products of cholecystokinin octapeptide proteolysis interact with central CCK receptors. Neurosci Lett (in press)
Tamminga CA, Lewitt P, Chase TN (1985a) Cholecystokinin and neurotension gradients in human cerebrospinal fluid. Arch Neurol 42:354–355
Tamminga CA, Chase TN, Knight M (1985b) Cholecystokinin octapeptide in the treatment of neuropsychiatric disease. In: Barchas JD, Bunney WE (eds) Perspectives in psychopharmacology (in press)
Vanderhaeghen JJ, Signeau JC, Gepts W (1975) New peptide in the vertebrate CNS reacting with antigastrin antibodies. Nature 257:605
Verbanck PMP, Lotstra F, Gilles C, Linkowski P, Mendlewicz J, Vanderhaeghen JJ (1984) Reduced cholecystokinin immuno-reactivity in the cerebrospinal fluid of patients with psychiatric disorders. Life Sci 34:67–72
Wagman AMI, Keller K, Summerfelt A, Carpenter WT (1983) Neuroleptic effects upon visual evoked potentials of schizophrenics. Presented at Eastern Psychol Assn (1983)
Zetler G (1983) Neuroleptic-like effects of ceruletide and cholecystokinin octapeptide: interactions with apomorphine, methylphenidate and picrotoxin. Eur J Pharmacol 94:261–270
Author information
Authors and Affiliations
Additional information
Offprint requests to: C.A. Tamminga
Rights and permissions
About this article
Cite this article
Tamminga, C.A., Littman, R.L., Alphs, L.D. et al. Neuronal cholecystokinin and schizophrenia: pathogenic and therapeutic studies. Psychopharmacology 88, 387–391 (1986). https://doi.org/10.1007/BF00180843
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00180843