Does the cholecystokinin antagonist proglumide possess antipsychotic activity?

doi:10.1016/0165-1781(86)90056-9

Psychiatry Research

Volume 18, Issue 1, May 1986, Pages 1-7

https://doi.org/10.1016/0165-1781(86)90056-9 Get rights and content

Abstract

Cholecystokinin (CCK), a neuropeptide which fulfills almost all criteria for neurotransmitter status, has been co-localized with dopamine in midbrain mesolimbic and mesocortical neurons that have been implicated in the pathogenesis of schizophrenia. Preclinical research suggests that CCK may in part act to enhance central dopaminergic activity. In an attempt to evaluate the role of CCK relative to the dopamine hyperactivity hypothesis of schizophrenia, in the present investigation the putative CCK receptor antagonist, proglumide, was administered to four schizophrenic patients in a double-blind, placebo-controlled study. All patients were receiving concurrent neuroleptic medication, but were still significantly symptomatic. Proglumide was without effect on the patients' psychosis ratings. Potential reasons for this negative finding are discussed.

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Cited by (19)

Involvement of Neuropeptide Systems in Schizophrenia: Human Studies
2007, International Review of Neurobiology
Citation Excerpt :
On the basis of the observation that CCK and CCK analogs stimulate midbrain DA cell firing (Skirboll et al., 1981), the antipsychotic potential of the CCK receptor antagonist proglumide was examined. Three clinical trials failed to demonstrate efficacy of proglumide in the treatment of schizophrenia (Hicks et al., 1989; Innis et al., 1986; Whiteford et al., 1992). The few clinical studies evaluating gastrin found no evidence of a role for this peptide in the pathophysiology of schizophrenia (Detera‐Wadleigh et al., 1987; Gjerris et al., 1984; Rafaelsen and Gjerris, 1985).
Neuropeptides are heterogeneously distributed throughout the digestive, circulatory, and nervous systems and serve as neurotransmitters, neuromodulators, and hormones. The chapter discusses that neuropeptides are phylogenetically conserved and have been demonstrated to regulate numerous behaviors. They have been hypothesized to be pathologically involved in several psychiatric disorders, including schizophrenia. On the basis of preclinical data, numerous studies have sought to examine the role of neuropeptide systems in schizophrenia. This chapter reviews the clinical data, linking alterations in neuropeptide systems to the etiology, pathophysiology, and treatment of schizophrenia. It describes the clinical trials of data from cerebrospinal fluid (CSF), postmortem and genetic studies. Despite the inherent difficulties associated with human studies, several findings are noteworthy. Postmortem studies support disease-related alterations in several neuropeptide systems in the frontal and temporal cortices. Finally, the only compounds that act directly on neuropeptide systems that have demonstrated therapeutic efficacy in schizophrenia are neurokinin receptor antagonists.
Biological actions of cholecystokinin
1994, Peptides
Cholecystokinin (CCK) has emerged as an important mammalian neuropeptide, localized in peripheral organs and in the central nervous system. This review presents an overview of the molecular aspects of CCK peptides and CCK receptors, the anatomical distribution of CCK, the neurophysiological actions of CCK, release of CCK and effects of CCK on release of other neurotransmitters, and the actions of CCK on digestion, feeding, cardiovascular function, respiratory function, neurotoxicity and seizures, cancer cell proliferation, analgesia, sleep, sexual and reproductive behaviors, memory, anxiety, and dopamine-mediated exploratory and rewarded behaviors. Human clinical studies of CCK in feeding disorders and panic disorders are described. New findings are presented on potent, nonpeptide CCK antagonists, selective for the two CCK receptor subtypes, which demonstrate that endogenous CCK has biologically important effects on physiology and behavior.
CCK antagonists: Pharmacology and therapeutic interest
1994, Pharmacology and Therapeutics
CCK was first identified and characterized in the digestive tract where it is known to be a factor involved in the control of gut motility. Later, CCK and CCK receptors were identified in regions of the central nervous system that are associated with the control of emotion, motivation and sensory processing. The recent discovery and development of CCK-receptor antagonists having selective affinity for either CCK_A or CCK_B receptors has led to a better understanding of the functional role of CCK and its binding sites in the brain and periphery. Some of these compounds are being examined in man for their therapeutic usefulness in mental as well as in digestive disorders. This review will highlight the results from both basic and clinical investigations that have examined the effects of selective CCK receptor ligands. The focus will be on the central nervous system pharmacology of CCK antagonists and the involvement of CCK in gastrointestinal and colonic motility.
A neuroleptic-like effect of ceronapril on latent inhibition
1992, Neuroscience
Three experiments that used a latent inhibition procedure to investigate the effects of ceronapril on attentional processes in the rat are reported. Latent inhibition is a behavioural paradigm in which prior exposure to a stimulus with no significant consequences retards subsequent conditioning to that stimulus when it is paired with reinforcement. Latent inhibition reflects a process of learning to ignore, or tune out, irrelevant stimuli, and has been suggested as an animal model of the attentional processes disrupted in the acute phase of schizophrenia. In animals, latent inhibition is disrupted by the administration of low doses of amphetamine and enhanced by the administration of neuroleptics. Ceronapril is an angiotensin converting enzyme inhibitor that has been shown to retard the breakdown of central cholecystokinin. It has been proposed that elevation of cholecystokinin levels in the brain may possess neuroleptic-like properties. We assessed this possibility by determining the effects of ceronapril on latent inhibition using a conditioned emotional response procedure, consisting of three stages: pre-exposure, in which the to-be-conditioned stimulus, a tone, was repeatedly presented without reinforcement; conditioning, in which the pre-exposed stimulus was paired with shock; and test, where latent inhibition was indexed by animals' suppression of licking during tone presentation. In Experiment 1, 20 tone pre-exposures were given, and conditioning consisted of five tone-shock pairings; we assessed the effects of 0.005 mg/kg, 0.05 mg/kg and 0.5 mg/kg ceronapril, compared with vehicle injections. In Experiment 2, five tone pre-exposures were given, and conditioning consisted of two tone-shock pairings: we assessed the effects of 0.05 mg/kg ceronapril, compared with vehicle injections. Both procedures have been shown to be insufficient to produce latent inhibition in normal animals, in the one case because there are enough conditioning trials to overcome the effects of pre-exposure, and, in the other, because there is insufficient pre-exposure to produce an effect. Accordingly, in the present experiments, latent inhibition was absent in vehicle controls, but, in marked contrast, animals treated with 0.05 mg/kg ceronapril exhibited latent inhibition. Experiment 3 used a procedure that yields latent inhibition in normal animals, consisting of 40 tone pre-exposures and two tone-shock pairings; we assessed the effects of 0.05 mg/kg ceronapril on latent inhibition as well as on the disruption of latent inhibition produced by 1 mg/kg amphetamine. Ceronapril (0.05 mg/kg) significantly enhanced latent inhibition with respect to vehicle controls. This enhancing effect was not seen in rats given 1 mg/kgd-amphetamine.
Ceronapril thus produces effects on attentional learning that have hitherto been shown only with typical and atypical neuroleptics, and may therefore possess some antipsychotic properties.
Cholecystokinin-dopamine intearctions
1991, Trends in Pharmacological Sciences
Cholecystokinin (CCK) coexists with dopamine in a large proportion of the ventral tegmental and substantia nigra neurons in rodents primates. In this review Jacki Crawley integrates the neurophysiological, behavioral, and release studies which demonstrate both excitatory effects of CCK, and facilitatory modulating effects of CCK on the inhibitory actions of dopamine, in the mesolimbic pathway. Nonpeptide antagonists selective for the CCK_A and CCK_B receptors have recently been developed, and provide long-awaited tools to test hypotheses about the role of endogenous CCK as a modulator of dopaminergic function, and the potential of CCK-based drugs as treatments for neuropsychiatric disorders.
Repeated naloxone administration in schizophrenia: A phase II world health organization study
1989, Biological Psychiatry
In the context of a previous WHO collaborative study, six research centers reported that naloxone (0.3 mg/kg) produced significant improvement in symptomatology in neuroleptictreated patients. In the current Phase II WHO study, repeated (4 days) naloxone (0.3 mg/kg) administration was performed in schizophrenic patients (n = 43) from five WHO collaborating centers using a double-blind, placebo-controlled design. Both naloxone and placebo administrations were associated with significant reductions in symptoms. Naloxone, however, was not superior to placebo. These data are discussed in relation to endorphin hypotheses of schizophrenia.

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Does the cholecystokinin antagonist proglumide possess antipsychotic activity?

Abstract

Life Sciences

Peptides

European Journal of Pharmacology

Biological Psychiatry

Life Sciences

Progress in Neuro-Psychopharmacology and Biological Psychiatry

Neuroscience