Cholecystokinin and Psychiatric Disorders

PHARMACOLOGY AND PATHOPHYSIOLOGY eNS Drugs 1997 Aug. 8 (2). 134-152 1172-7047/9710008{)134/SQ9 50/0

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Cholecystokinin and Psychiatric Disorders Role in Aetiology and Potential of Receptor Antagonists in Therapy

Jakov Shlik,l Eero Vasar2 and Jacques Bradwejn3

1 Department of Psychiatry, University of Tartu, Tartu, Estonia 2 Department of Physiology, University of Tartu, Tartu, Estonia 3 Psychobiology and Clinical Trials Research Unit in Anxiety, Clarke Institute of Psychiatry,

University of Toronto, Toronto, Ontario, Canada

Contents Summary . . . . . . . . . . . . . . . . . . . . . . . . 134

136 136 136 138 138 139 139 144 145 146

1. Neurobiology of Cholecystokinin. . . . . . . . . . . 1 .1 Role of Cholecystokinin as a Neurotransmitter 1.2 Cholecystokinin Receptors . . . . . . . 1.3 Cholecystokinin Receptor Agonists ...". 1.4 Cholecystokinin Receptor Antagonists ....

2. Potential Neuropsychiatric Applications of Cholecystokinin Antagonists . 2.1 Anxiety.... 2.2 Depression .. 2.3 Schizophrenia

3. Conclusion .,..

Summary Cholecystokinin (CCK) is one of the most abundant neuropeptides in the brain. It is found in the highest levels in cortical and limbic structures and also in the basal ganglia. Two subtypes of CCK receptors have been described in the brain and gastrointestinal tissues. CCKA (alimentary subtype) receptors are mainly located in the gastrointestinal tract, regulating secretion of enzymes from the pancreas and emptying of the gallbladder. However, CCKA receptors are also found in several brain regions, with the highest densities in structures poorly protected by the haematoencephalic barrier (the area postrema, nucleus tractus solitarius and hypothalamus). The distribution ofCCKB (brain subtype) receptors overlaps with the localisation of CCK and its mRNA in different brain areas, with the highest densities in the cerebral cortex, basal ganglia, nucleus accumbens and forebrain limbic structures.

Both subtype of CCK receptor belong to the guanine nucleotide-binding protein(0 protein)-linked receptor superfamily containing 7 transmembrane domains. Signal transduction at CCK receptors is mediated via Oq protein-related activation of phospholipase C and the formation of inositol I ,4,5-triphosphate (lP3) and 1,2-diacylglycerol (DAO). Recent cloning of CCKA and CCKB receptors has shown that mRNA for both receptors is distributed in the same tissues as estab-

CCK Antagonists in Psychiatric Disorders 135

Ii shed in radioligand binding and receptor autoradiography studies, with few exceptions.

The existence of mUltiple CCK receptors has fuelled the development of selective CCKA and CCKB receptor antagonists. These antagonists belong to distinct chemical groups, including dibutyryl derivatives of cyclic nucleotides, amino acid derivatives, partial sequences and derivatives of the -COOH terminal sequence heptapeptides of CCK, benzodiazepine derivatives, 'peptoids' based on fragments of the CCK molecule, and pyrazolidinones. At the present time, the compounds of choice for blockade of the CCKA receptor are lorglumide, devazepide and lintitript (SR27897). L-365,260, CI-988, L-740,093 and LY288513 are the drugs most widely used to block CCKB receptors.

Studies with CCK antagonists (and agonists) in animals and humans suggest a role for CCK in the regulation of anxiety and panic. The administration of CCK agonists [ceruletide (caerulein), CCK-4, pentagastrin] has an anxiogenic action in various animal models and in different animal species. However, the anxiogenic action of CCK agonists is restricted to nonconditioned (ethological) models of anxiety, with very limited activity in the 'classical' conditioned models. Pharmacological studies have revealed that CCKB receptors are the key targets in the anxiogenic action of CCK agonists. Nevertheless, CCKB antagonists displayed very little activity, if any at all, in these models, but strongly antagonised the effects of CCKB agonists. The anxiogenic/panicogenic action of CCKB agonists (CCK-4, pentagastrin) is even more pronounced in human studies, but the effectiveness of CCKB antagonists as anxiolytics remains unclear. Clinical trials performed to date have provided inconclusive data about the anxiolytic potential of CCKB receptor antagonists, probably because of limiting pharmacokinetic factors.

The results of some animal experiments suggest a role for CCK in depression. The administration of CCKB antagonists causes antidepressant-like action in mouse models of depression. However, human studies replicating this result have yet to be carried out.

A prominent biochemical alteration in schizophrenia is a reduction of CCK levels in the cerebral cortex. This change may be related to the loss of cortical neurons, due to the schizophrenic process itself. In animal studies (mainly in mice), administration of CCK agonists and antagonists has been shown to be effective in several models, reflecting a possible antipsychotic activity of these drugs. However, the data obtained in human studies suggest that CCK agonists and antagonists do not improve the symptoms of schizophrenia. Taking into account the reduced levels of CCK and its receptors found in schizophrenia, treatments increasing, but not blocking, brain CCK activity may be more appropriate.

Cholecystokinin (CCK), which belongs to the family of gut-brain peptides, was originally discovered in the gut and shown to mediate pancreatic secretion and contraction of the gall bladder. CCK was initially characterised as a 33-amino-acid sequence peptide. However, it is now known that the peptide is present in a variety of biologically active

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molecular forms.[l] These different forms are cleaved from a 115-amino-acid precursor molecule (prepro-CCK), and include CCK-58, CCK-39, CCK-33, CCK-22, sulphated CCK-8 (CCK-8s) and CCK-7, unsulphated CCK-8 and CCK-7, and CCK-5 and CCK-4.

CCK was first described in the mammalian CNS

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in 1975 as a gastrin-like immunoreactive material,f2] and is now generally believed to be the most widespread and abundant neuropeptide in the CNS. [I] Although all short molecular forms are present in the brain, the majority of neuronal CCK is in the form of CCK-8sP,4] Gastrin and CCK have identical -COOH terminal penta-peptide sequences. It has been proposed that the brain contains at least 3 subpopulations of CCK neurons with different posttranslational pathways)S,6] This approach would suggest that different CCK peptides can function independently in distinct neuronal settings. In contrast, others believe that the existence of mUltiple forms of CCK in the brain can be attributed to variable and/or incomplete post-translational processing of the precursor molecule)?]

High levels of CCK or CCK mRNA have been identified throughout the brain, including in the cerebral cortex, olfactory bulb, olfactory tubercle, hippocampus, basal ganglia, hypothalamus and periaquaductal gray)8-1O] Considerable evidence suggests that CCK functions as a neurotransmitter and, in this context, iontophoretic application of the peptide to neurons has generally been found to produce excitatory effects.[I] Moreover, CCK is colocalised with other neurotransmitters such as dopamine, substance P, eokephalin, 'Y-aminobutyric acid (GABA), oxytocin and corticotrophin-releasing factor.

1. Neurobiology of Cholecystokinin

1.1 Role of Cholecystokinin as a Neurotransmitter

High levels of CCK-like immunoreactivity are present in synaptosomal preparations)II,12] CCK has been shown to be synthesised de novo in the brain'p3] It can be released in a calcium (Ca++)-dependent manner from brain slices or synaptosomes exposed to depolarising stimuli)I2,14,IS] Furthermore, specific high affinity binding sites for CCK are widely distributed throughout the CNS)16] CCK has been shown to induce excitation of central neurons.[17-19] However, inhibitory postsynaptic effects have also been demonstratedPO-22] This

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Shlik et al.

is in accordance with morphological findings suggesting that CCK is present in both excitatory and inhibitory neurons.[23]

The mechanism of termination of the action of CCK is less clear, but selective uptake into the synaptosomal fraction in vitro was recently demonstratedP4] In addition, evidence of CCK-8-degrading enzymes has now been found in rat brain.[I] CCK degradation occurs through the action of a membranebound aminopeptidase.

1.2 Cholecystokinin Receptors

Two types of high affinity CCK binding sites, initially termed 'peripheral' and 'central' receptors (table I), were characterised in 1980 by several groupsPS-28] At peripheral binding sites, CCK-8s was the minimal sequence for high affinity binding, whereas at central binding sites, CCK-4, gastrin and un sulphated CCK-8 showed binding activity, albeit at potencies comparable with CCK-8s.

Although these early studies did not hint at heterogeneity of brain CCK receptors, later research on the electrophysiological and behavioural effects of CCK fragments strongly suggested that peripheraltype CCK receptors were also present in brain tissue. Based on the autoradiographical studies of Moran and colleaguesY6] CCK receptors have since been classified as CCKA (alimentary subtype) and CCKB (brain subtype), independent of their localisation. Thus, it was shown that CCKA receptors do occur in certain brain areas, namely in the area postrema, nucleus tractus solitarius and interpeduncular nucleus. Further, radioligand and electrophysiological studies revealed an even more widespread distribution of CCKA receptors; these sites have been found in the dorsal raphe, nucleus accumbens septi, substantia nigra and ventral tegmental areaP9-32] CCKB receptors are widely distributed in the brain, with the highest level in the striatum, cerebral cortex and limbic system,[33] but they are also found in the stomach. CCKB receptors have, for some time, caused confusion because of their similarity to gastrin receptors.

Both CCKA and CCKB receptors possess 7 transmembrane domains and appear to belong to

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CCK Antagonists in Psychiatric Disorders

Table I. Characteristics of cholecystokinin (CCK) receptors Nomenclature CCKA receptor Alternative names Peripheral subtype

CCKB receptor Central subtype CCKs/gastrin receptor

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Potency order of CCK agonists Ceruletide (caerulein) > CCK·8s » gastrin = CCK-4 Ceruletide > CCK-8s > gastrin = CCK-4 Ceruletide Agonists

Antagonists

Effector Gene

Ceruletide CCK-8s A71623 A70874 JMV-180

Proglumide Devazepide Lorglumide Lintitript (SR27897)

G-protein q/11 CCKA

CCK-8s CCK-8us CCK-4 Pentagastrin BC264 BC197 Proglumide L-365,260 L-740,093 LY288513 LY262691 CI-988 G-protein ql11 CCK8

Structural information

Location in chromosomes

428-amino-acid sequence human P32238 7TM 444-amino-acid sequence rat P30551 7TM Human chromosome 4

447-amino-acid sequence human P32239 7TM 452-amino-acid sequence rat P30553 7TM Human chromosome 11

Mouse chromosome 5 Mouse chromosome 7 Distribution Gall bladder, pancreas, pylorus, intestine, spinal cord,

vagus nerve, limited brain areas (nucleus tractus solitarius, area postrema, nucleus interpeduncularis, posteromedial part of nucleus accumbens)

Throughout the brain (with the highest densities in the cerebral cortex, nucleus caudatus, anterolateral part of nucleus accumbens), stomach, vagus nerve Mediates actions of CCK on increases in neuronal firing rates, nociception, anxiety, respiration, inhibits dopamine-mediated behaviours and dopamine release

Functions Mediates actions of CCK on gall bladder contraction, secretion of pancreatic enzymes, gastric emptying, inhibits feeding and respiration, potentiates dopamine-mediated behaviours and dopamine release in shell of nucleus accumbens

Abbreviations: Px = SwissProt database accession numbers; s = sulphated; TM = transmembrane domains; us = unsulphated.

the guanine nucleotide-binding protein-(G protein)linked receptor superfamily, with considerable ammo acid sequence similarities to other members of I.he family.

The signal transduction mechanism of CCK receptors has been best characterised in pancreatic acini, where CCK stimulates digestive enzyme release. Occupation of cell surface membrane CCKA

leceptors by CCK initiates coupling to pertussis toxin-insensitive G proteins,f34,351 presumably members of the Gq family known to be present in the rat pancreas.f36] G protein activation and subsequent coupling to phosphoinositol-specific phospholipase C (PLC)l37-40] leads to the hydrolysis of phosphat, dylinositol biphosphate and the formation of inositol 1,4,5-triphosphate (IP3) and 1,2-diacylglycerol C~AG).l4J-441 An increase in IP, results in the re-

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lease of intracellular Ca++,f45,46J while DAG activates protein kinase C (PKC), with subsequent translocation from the cytosol to the membrane.l47]

The signal-transduction cascade for CCKB/gastrin receptors has been less well characterised, largely because of the difficulty in working with isolated neurons expressing CCKB receptors or isolated gastric mucosal cells expressing gastrin receptors. In isolated canine, porcine or rabbit parietal cells, gastrin receptors, like CCKA receptors, couple to pertussis toxin-insensitive G proteins,[48] causing activation of PLC, formation of IP3 and DAG, release of intracellular Ca++ and translocation and activation of PKCJ49,50] In cultured neonatal rat brain cells, CCK-8 stimulated the turnover of phosphoinositide and increased IP3labelling, an effect that seemed to involve both CCKA and CCKB


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receptorsJ51] One study of CCKB/gastrin receptors, using synaptoneurosomes from guinea-pig cortex, did not demonstrate a CCK analogue-stimulated increase in adenylate cyclase or PLC, although Ca++ was released from intracellular stores, possibly via a G-protein-independent mechanismJ52] Some of the CCKB receptors may be linked to Ca++ channels, and their activation has been shown to increase intracellular free Ca++ levels in rat glioma cells (C6-cells)[53] and in cultured rat striatal neurons.[54]

Recently, both CCKA [55,56] and CCKB/gastrin receptors[57,58] of several species have been cloned, It was revealed that the canine parietal cell gastrin receptors and brain CCKB receptors are highly homologous, if not identicaU57] Indeed, a recently reported analysis of human genomic DNA indicates that a single gene encodes both the brain and the stomach CCKB/gastrin receptors.[58] The gene encoding the CCKA receptor maps to a syntenic region of human chromosome 4 and mouse chromosome 5, The CCKB receptor gene, on the other hand, resides on a syntenic region of human chromosome II and distal mouse chromosome 7J59]

Localisation of the CCK receptors with 2 dopamine receptors, dopamine D5 (4p15.2-p15.3) and D4 (lIp15), suggests the interesting possibility of co-involvement of dopamine and CCK receptors in neuropsychiatric disorders.l59]

Three affinity states for the CCKA receptor in the pancreas have long been suggested to exist,[60] but there is as yet no evidence for heterogeneity. Different affinity states for CCKB receptors have also been suspected,[61,62] but the evidence for these is still scarce. However, the alternative splicing of the CCKB/gastrin receptor gene at exon 4 results in expression of mRNAs for 2 isoforms of the receptor in human gastric membranesJ63] These isoforms may differ in signal transduction at the second messenger level, since the alternative splicing affects the putative third intracellular loop, The use of in situ hybridisation technology revealed a regional distribution of CCK receptor mRNA, which generally parallels the known distribution of CCKA

and CCKB receptorsJ64]


Shlik et al.

1.3 Cholecystokinin Receptor Agonists

Innis and Snyder[26] clearly demonstrated that the subtypes of CCK receptors, now called CCKA

and CCKB receptors, may be differentiated according to their affinity for CCK fragments and analogues. The minimal active fragment at the CCKA

receptor is CCK-8s, whereas CCKB receptor binding does not require sulphation and the minimal active fragment is CCK-4.[65] Thus, CCK-8s is a nonselective CCK receptor agonist. Another nonselective agonist, the amphibian decapeptide ceruletide (caerulein), has been widely used in pharmacological studies due to its similar effects on CCK receptors and possibly better resistance to proteolytic cleavage, Unsulphated CCK-8, pentagastrin, CCK-4, BC264 and BC197 have served as selective CCKB agonists, whereas selective CCKA agonists (A7l623 and A70874) became available recently. However, the development of selective antagonists has been of much greater importance to research on the functional significance of CCK receptor subtypes (see section 1.4).

1 .4 Cholecystokinin Receptor Antagonists

Several chemically distinct groups of CCK receptor antagonists have been synthesised,[65] including dibutyryl derivatives of cyclic nucleotides, amino acid derivatives, partial sequences and derivatives of the -COOH terminal sequence heptapeptides of CCK, benzodiazepine derivatives, 'peptoids' based on fragments of the CCK molecule, and pyrazolidinones. Proglumide, a nonselective CCK receptor antagonist and derivative of glutaramic acid,[66] was widely used in pharmacological studies until the introduction of selective nonpeptide CCK receptor antagonists.

At the present time, the compounds of choice for the blockade of the CCKA receptor are: (i) lorglumide (formerly CR-1409), an analogue of proglumide, and (ii) devazepide (formerly L-364,7l8 and MK-329), a benzodiazepine derivative, with affinity 2 to 3 times higher for CCKA receptors than for CCKB receptorsJ67,68] Recently, another chem-



ically distinct CCKA receptor-selective antagonist [lintitript (SR27897)] was synthesised)69]

Chemically distinct nonpeptide CCKB receptorselective antagonists are also available. The pharmacologically best characterised is L-365,260, an analogue of devazepide)70] Recently, a new benzodiazepine derivative, L-740,093, became available. This is a water soluble CCKB receptor antagonist, which has improved bioavailability and readily crosses the blood-brain barrierPl] CI-988 (formerly PD134308)[72] and LY262691[73] belong to the 'peptoid' and pyrazolidinone groups of CCKB receptor antagonists, respectively. In general, it is nearly impossible to distinguish pharmacologically between CCKB and gastrin receptors. Only the pyrazolidinone series of CCKBigastrin antagonists contain some compounds that have some selectivity, having up to 35-fold higher affinity for brain CCKB binding sites compared with the stomach gastrin receptors)73]

2. Potential Neuropsychiatric Applications of Cholecystokinin Antagonists

2.1 Anxiety

2. 1. 1 Animal Models

CCK Agonists and Anxiogenesis Fekete and co-workers[74] were the first to dem

onstrate the anxiogenic potential of neuronal CCK on the basis of animal experiments, even though other authors had earlier described anxiogenic-like effects of administered CCK peptides.[20,75] Further studies have shown that CCK peptides administered systemically or intracerebrally produce anxiogeniclike effects in several species, including mice, rats, guinea-pigs, cats and monkeysP4,76-83] CCK receptor agonists inhibit exploratory behaviour of mice and rats in the elevated plus-maze test, decrease the time spent and locomotor activity in the light compartment of the light/dark compartment test, and mpport acquisition and retention in fear-motivated I:ests. [84] Peripherally injected CCK can produce coniitioned place aversion in food-deprived rats)85] (:CK peptides also increase defensive burying in

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ratsP6] CCK-4 treatment has been shown to suppress feeding in novel situations and to increase the number of distress calls in the ultrasound vocalisation test using rat pups separated from the mother. [82]

However, the anxiogenic-like effects of administered CCK peptides in animal experiments have not been observed by all investigators, and this considerable body of negative findings should not be ignored. CCK-4 failed to be aversive in an operant responding paradigm in rats,[86] and pentagastrin did not induce anxiety in monkeys.[87] It appears that the dose efficacy and behavioural patterns after CCK challenge depend upon the baseline anxiety of the animal and on its hierarchical position in its social group. In monkeys, the 'uptight' animals, typically restless, submissive to threat and excessively reactive to the environment, become anxious after low doses of CCK-4,[80] while the behaviour of basically calm conspecifics seems to be rather different after CCK-4 injection. These findings could suggest that CCKB receptor stimulation induces anxiety only in animals already in distress.

Anxiolytic Effects of CCK Antagonists The nonselective CCK receptor antagonist proglu

mide, and the selective CCKB receptor antagonists L-365,260, CI-988 and LY262691, show anxiolyticlike effects in several animal anxiety tests.[65] The selective CCKA receptor antagonists lorglumide and devazepide show similar properties, but at doses that probably also stimulate CCKB receptors.[65.78] However, in some laboratories, the anxiolytic effect of a CCKB antagonist as a single treatment has not been evident.[78.88-90] These negative findings were confirmed by Dawson et al.,[91] who demonstrated the ineffectiveness of 3 CCKB receptor antagonists (L-365,260, L-740,093 and CI-988) in 3 rat anxiolytic screens sensitive to benzodiazepines (the elevated plus-maze, conditioned suppression of drinking and conditioned emotional response tests).

However, since peptide neurotransmission is believed to be released by bursting or high-frequency neuronal activity, peptide antagonists may not necessarily show any effect under normal tonic activ-

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ity.[92] In this context, it is important to stress that the effect of established anxiogenic drugs, both CCK agonists and GABA antagonists, can be blocked by CCK receptor antagonists.l65.78.80.88.93.94]It should also be noted that the exposure of rats to the elevated plus-maze is not a sufficiently strong stress to increase the levels of CCK mRNA in the amygdala and hippocampus.l95] By contrast, the anxiogenic benzodiazepine inverse agonist FG-7142 increased CCK gene expression in these limbic structures. Administration of this benzodiazepine receptor ligand, like other anxiogenic manipulations in rats, also increased the number of CCK binding sites in the frontal cortex.[96-98] Exposure of rats to the odour of a cat significantly increased the levels ofCCK-4 in various brain structures and this effect was blocked by pretreatment with the CCKB antagonist L-365,260)99] Accordingly, anxiogenic manipulations in rats can induce CCK gene expression, increase the levels of CCK-4 and the number of CCK receptors. Whether these effects can be prevented by CCKB receptor antagonism remains to be determined. Interestingly, recent experiments demonstrated that exposure of rats to the decapitation of conspecifics led to the upregulation of CCK receptors in stressed animals, reflected in an increase in [3H]propionylated-CCK-8 binding in the frontal and cerebral cortex that could not be blocked by diazepam pretreatment.l 100]

There appears to be little doubt that CCK receptor ligands do influence emotions, since they are active in different behavioural paradigms in many species. However, data on the efficacy of CCK receptor antagonists measured using routine anxiety tests should be interpreted with caution. As mentioned above, some investigators have not observed any effect of CCK receptor antagonists on exploratory behaviourJ78.88-91] On the other hand, the most pronounced anxiolytic-like action of CCKB receptor antagonists has been demonstrated using tests based on exploratory activity, frequently exploited to measure anxiety in rodents. It is frequently not considered that exploratory behaviour is dependent on the interplay between neophobia and exploratory drive, the latter depending upon

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Shlik et al.

multiple intrinsic and environmental factors.[84] The potent anxiolytic effects of CCK receptor antagonists per se (without a previous defined anxiogenic challenge) have been demonstrated using tests of exploratory activity, but not in other tests. [72. lDl] Thus, CCKB antagonists are almost inactive in classic anxiety tests in which conflict is created by delivering direct punishment, e.g. by electric footshock.l lD2] It has been suggested that this effect of CCKB receptor antagonists on exploratory behaviour is due to the additional effect of the motivation systems that mediate curiosity.[88.98]

CCK and Dopamine Co-localisation of CCK and dopamine in the

ventral tegmental area and the ascending mesolimbic pathways suggest that CCK could act as a neuromodulator of dopaminergic neurotransmission.[I03.104] These dopaminergic pathways have been closely related to motivational mechanisms and reward[105] and, thus, CCK would have a place in the regulation of motivated behaviours. Some of the anxiogenic-like effects of CCK are almost certainly mediated by these mechanisms. For example, CCK injected into the posteromedian part of nucleus accumbens reduces novelty-related exploration through CCKA receptors, an effect probably related to the reduction of dopamine metabolism and mediated by modulation of presynaptic dopamine D2 receptors.[106]

2.1.2 Human Studies

CCK-Induced Panic Attacks Recent work, primarily conducted at the St.

Mary's Hospital, McGill University (Montreal, Canada), has led to a hypothesis that alterations of CCK-ergic mechanisms contribute to the pathophysiology of panic disorder. The starting point for these studies was the electrophysiological experiment of Bradwejn and de Montigny[107] which demonstrated that benzodiazepine receptor agonists selectively and specifically antagonised CCK-8sinduced excitation of hippocampal pyramidal neurons in rats. These studies provided evidence that anxiolytic benzodiazepines could antagonise the central action of a neuropeptide, and it was proposed

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that benzodiazepine-mediated antagonism of CCKinduced excitation might be an important mechanism by which benzodiazepines exert their clinically relevant action.

More importantly, the observation that an anxiolytic drug could block the excitatory action of CCK raised questions about whether CCK might be an endogenous anxiogenic compound. Two pilot studies were conducted to address this question using the tetrapeptide form of CCK (CCK-4). One was in patients with panic disorder, and the other was in healthy individuals with no personal or family history of panic attacks. The decision to administer CCK-4 to patients with panic disorder was based on anecdotal data presented at a conference in 1984 by the biochemistJens Rehfeld who, in the course of investigating the neuroendocrine effects of CCK-4 in healthy humans, noted that CCK-4 .produced 'side effects' such as anxiety, dyspnoea and depersonalisation.[6] These effects were strikingly similar to symptoms experienced by patients with panic disorder during their spontaneous panic attacks.

de Montigny[I08] first reported that exogenous CCK-4 produced panic-like attacks in healthy volunteers. Bradwejn and colleaguesl1091 administered CCK-4 to patients with a current-point diagnosis of panic disorder, using a double-blind placebocontrol methodology. Bolus injections of CCK-4 (50~g) precipitated a panic attack, as defined by DSM-III criteriall IOJ and patient self-report, within 1 minute following administration in 11 patients studied, whereas placebo did not induce panic in any patients. CCK-4 treatment elicited an average of 12 symptoms per patient, the most common symptoms being dyspnoea, palpitations/rapid heart beat, chest pain/discomfort, faintness, dizziness, paraesthesia, hot flushes/cold chills, nausea/abdominal distress, anxiety/fear/apprehension and fear of losing control.

It has been found that response to CCK-4 reliably differentiates patients with panic disorder from healthy controls with no personal or family history of panic attacks. In a double-blind, placebocontrolled study, the patients with panic disorder


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experienced a greater number of and more intense symptoms following challenge with 2 doses of CCK-4 (25 and 50~g).llIll In addition, the incidence of panic attacks was markedly higher in patients than in controls following injection of 25~g (91 versus 17%) and 50~g (100 versus 47%) ofthe peptide. Interestingly, the number and intensity of symptoms as well as the symptom profile were remarkably similar in both patients and healthy individuals who experienced panic after the 50~g dose of CCK-4, suggesting that the enhanced response in patients could not be readily attributed to a tendency to overendorse symptoms. A comparison of the effects of CCK-4 (25~g) with those of a single inhalation of 35% CO2 has been performed in healthy volunteers and patients with panic disorder.l" 2,II3) These studies demonstrated quite similar panicogenic profiles, of CCK-4 and CO2, although CCK-4 induced more intense symptoms of panic and a higher rate of panic attacks in the patients, It will be interesting in future studies to compare CCK-4 with other panicogenic challenges, particularly the frequently employed sodium lactate infusion.

The CCK-4 challenge studies were corroborated by the studies of Abelson and colleagues[114) and van Megen and colleagues, [115) using pentagastrin, a CCK agonist that incorporates the identical 4-amino-acid sequence of CCK-4. These authors found that pentagastrin provoked panic attacks with a higher frequency in patients with panic disorder than in healthy individuals, Moreover, patients with panic disorder were shown to have decreased levels ofCCK-8s in CSF relative to control individuals,l116] The levels of CCK-8s in lymphocytes were also significantly reduced in patients with panic disorder compared with healthy controls, [117] In a recent study, a genetic polymorphism in the CCKB receptor gene was examined in patients with panic disorder compared with healthy controls. Patients with panic disorder showed a significant excess of 2 alleles in the CCKB receptor gene,l118] These findings suggest anomalies in the CCK system in panic disorder.


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Anti-Panic Effect of CCK Antagonists Antipanic drugs block the effect of CCK-4.l119]

de Montigny[108] reported that pretreatment with lorazeparn attenuated CCK -4-induced panic attacks in healthy volunteers. More recently, it was demonstrated that the panicogenic effects of CCK-4 can be antagonised by long term treatment with imipramine. [120] Van Megen and colleagues[ 121] have shown that the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor fluvoxarnine decreased CCK-4-induced panic attacks in patients with panic disorder. In addition, treatment with another serotonin reuptake inhibitor, citalopram, reduced an enhanced sensitivity to CCK-4 in patients with panic disorderJl22]

Data on the panicogenic effects of CCK agonists raised the possibility that antagonists of these receptors may have therapeutic potential in panic -disorder, and a number of studies have assessed this issue. In 1 study, pretreatment of patients with the selective CCKB receptor antagonist L-365,260 (10 and 50mg) dose-dependently blocked CCK-4-induced panic attacks.l 123] Pretreatment with L-365,260 at the same doses also reversed both the autonomic and anxiogenic effects of pentagastrin in healthy volunteers. [I 24] When the action of another CCKB receptor antagonist, CI-988, was evaluated in healthy volunteers, there was a significant decrease in sum intensity scores and panic attack frequency induced by CCK-4 following administration of CI-988 100mg.l125]

These data apparently support the role of CCKB receptors in the mediation of the panicogenic-like action of CCK-4. However, in recent studies, pretreatment with CI-988 in doses up to 100mg failed to antagonise CCK-4-[126] or lactate-induced[127] panic in patients with panic disorder.

In another study, patients pretreated with L-365,260 50mg experienced significantly less anxiety following a sodium lactate infusion than those pretreated with placebo.l 128] In contrast to the effect on fear and apprehension, L-365,260 was unable to block the physical symptoms induced by sodium lactate. In a study involving healthy volunteers, L-365,260 had no effects on measures of anx-

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Sh/ik et al.

iety in a neutral setting over a 10-day treatment period using a dosage range of 2.5 to 25mg every 6 hours)129] Furthermore, treatment with L-365,260 did not result in any clinically significant improvement in patients with panic disorder.[130] The possible reasons for the lack of effect with L-365,260 are not clear, but the poor pharmacokinetic properties of this drug are the most plausible explanation.

Other Anxiety Disorders The action of CCK-4 seems not to be limited to

panic disorder, since patients with other anxiety disorders also exhibit an augmented behavioural response to CCK-4. Le Melledo et al.[131] established that women with premenstrual dysphoric disorder (PDD) responded with significantly higher intensity and frequency of panic attacks to the administration of CCK-4 compared with women without PDD. Moreover, patients with social phobia,[132,133] obsessive-compulsive disorder[134] and generalised anxiety disorder[135] also respond with increased anxiety to the administration of pentagastrin.

Therefore, the augmented behavioural response to CCKB agonists seems to apply to disorders associated with an expression of anxiety or panic attacks. The administration of CCKB agonists seems to unmask a hypersensitivity that cuts across diagnostic boundaries. The rate of behavioural responses to CCKB agonists of different anxiety disorders might be related to their likelihood of expressing non-provoked symptoms of anxiety or panic. That is, there might be a gradient in response, depending on clinical symptom expression, which might be the expression of gradient in hypersensitivity of the CCKB receptors.

The effect of the CCKB antagonist CI-988 has been assessed in patients with generalised anxiety disorder. In a placebo-controlled clinical trial, CI-988 did not demonstrate an anxiolytic effect superior to placebo) 136] However, a significant treatmentby-centre interaction and a highly variable placebo response rate in this study limit the interpretation of the results. The poor penetration of CI-988 through the haematoencephalic barrier must also be taken into account.[137]

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CCK Antagonists in Psychiatric Disorders 143

Table II. Involvement of cholecystokinin CCKB receptors in anxiety

Effect Rodents Monkeys Humans

Anxiogenic effects of CCKB agonists + ++ ++

Anxiogenic effects of CCKB agonists antagonised by CCKB antagonists ++ ++ ++

Anxiolytic effect of CCKB antagonists ? + ?

Enhanced sensitivity to CCKB agonists in anxious individuals ? ++ ++

Endogenous anomalies of CCK system in anxiety + ? + Symbols: ++ = significant evidence; + = moderate evidence; ? = no or questionable evidence.

Synthesis of Available Data Table II provides a summary of currently avail

able data on the role of CCK in the regulation of anxiety. Animal studies are in good accordance with human data, and indicate that while CCK agonists such as CCK-4 and pentagastrin have robust anxiogenic/panicogenic effects, CCKB receptor antagonists are not effective anxiolytics.l88,91,138,139] There are several ways to explain this discrepancy: • Subtypes of CCKB receptors, having different

roles in the regulation of anxiety, may exist. Recently, the effects of selective CCKB agonists, BC264 and BCl97 and the nonselective CCK agonist BDNL(a structural analogue ofCCK-8) were investigated in the rat plus-maze test. BDNL and BC197 induced an anxiogenic-like effect, whereas BC264 had no effect.l140] The behavioural effects of BDNL and BC197 were suppressed by CI-988, but not by L-365,260, also suggesting some subtype specificity for these CCKB receptor antagonists.[141] Data from competition experiments performed with [3H]propionylated BC264 and brain membranes of guinea-pig, mouse and rat showed a significantly better fit when analysed by a 2-site model than by a I-site model with BC 197, but not with BC264.[141] Furthermore, BC264 and BC197 were found to mediate different effects in the anterior nucleus accumbens in rats.[142] An analysis of L-365,260 competition curves from radioligand binding studies also suggested the existence of 2 CCKB/gastrin receptor subtypes. [143]

• CCK is believed to be released by bursting or high-frequency neuronal activity only.[138] This might mean that CCK antagonists are more ef-


fective in stressed animals. Indeed, CCK agonists and antagonists seem to cause stronger effects in rodents if they are under stress.l84] On the other hand, the effectiveness of CCK antagonists in conditioned models of anxiety is very limited.l91 ] Therefore, it is doubtful that this hypothesis can explain the low potency of CCK antagonists in animal models of anxiety.

• CCK interacts with various neurotransmitter systems that form the neural networks of anxiety [GAB A, serotonin, noradrenaline (norepinephrine), dopamine, glutamate, neuropeptide Y, nitric oxide]. The anxiogenic action of CCK receptor agonists and enhanced sensitivity to such agonists could be due to a 'downstream' action of CCK agonists on a system with which CCK interacts. However, this does not mean that CCK is not playing a global role in anxiety, since the anxiogenic/panicogenic action of CCK-4 in humans seems to cut across diagnostic boundaries in anxiety.

• The lack of therapeutic action of CCKB receptor antagonists in anxiety disorders seems to be related to the poor bioavailability of tested compounds (L-365,260, CI-988). However, the lack of action of L-740,093, which has improved bioavailability and brain penetration, does not support this suggestion. Another question of central importance concerns

the site(s) of action of CCK-4 in humans. Currently, there is no available evidence that CCK-4 crosses the blood-brain barrier, although the possibility exists that CCK-4 affects CCKB receptors in brain regions that are not fully protected by the blood-brain barrier. A possible neuronal circuit generating panic response to CCK-4 may involve


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brains tern structures, including the nucleus tractus solitarius, medullary nuclei and parabrachial nucleus, which are inter-related and connected to the locus coeruleus, an area postulated to playa role in panic attacksJl44] There are experimental data suggesting that CCK interacts with these brainstem mechanisms in modulating respiratory and cardiovascular functionsJl45] Accordingly, it may be argued that increases in cardiovascular activity in response to CCK-4 challenge may be the result of direct or indirect stimulation of CCK receptors in brainstem structures such as the nucleus tractus solitarius. In this case, the emotional symptoms following CCK-4 challenge may result from an action of CCK-4 on brainstem structures and a subsequent activation or inhibition of higher CNS regions mediated by neuronal projections. As these brainstem structures are not fully shielded by the bloodbrain barrier, CNS penetration by CCK -4 might not even be necessary for this action.

2.2 Depression

Relatively little is known about the role of CCK in depression itself, or in laboratory procedures predictive of antidepressant activity. The level of CCK in the CSF of patients diagnosed with depression has been assessed. Four reports have indicated that CCK levels are unchanged in patients with primary depression, endogenous depression and nonendogenous depressionJI46-149] In contrast, another study has shown that CCK levels are decreased in patients with bipolar depressionJl50] Suicide victims were found to have a higher density of CCK receptors in the frontal but not in the cingulate cortex, and the higher density was correlated with a poorer affinity for CCK.[151] The social isolation of rats caused an increase in anxiety and in the number of CCK binding sites in the cerebral cortexJ97] Another study found that electroconvulsive shock increased CCK levels in both the frontal and cingulate cortices of ratsJl52]

A possible interpretation of these results is that the increased density of CCK receptors in suicide victims may reflect decreased levels of CCK, as it was found in patients with bipolar depression. In-

© Adis International Umited. All rights reserved.

Shlik et al.

deed, electroconvulsive shock increases the levels of CCK in the cerebral cortex, which may desensitise CCK receptors. There is an obvious discrepancy between these findings and the antidepressant-like effects of CCKB antagonists in the mouse models as described below. It could be that the changes in the levels of CCK and its receptors in the frontal cortex are the correlates of impulsiveness rather than depression.

In olfactory bulbectomised rats, 4-week administration of the CCKB receptor antagonist CI-988 reduced immobility in a behavioural despair experiment and attenuated ambulation in an open-field test.[153] Similar effects have been noted with clinically established antidepressant drugs such as demethyl-imipramine, amitriptyline and mianserinJI54,155] Interesting results have been obtained with the selective CCKB agonists BC264 and BC 197, in the stressful conditioned suppression of motility in mice, an animal model used to select antidepressant drugs. These agonists accentuated the suppression of motility in shocked mice, an effect that was inhibited by L-365,260. Moreover, L-365,260 alone decreased motor inhibition in shocked mice. This antidepressant-like effect was suppressed by naltrindole, a selective antagonist of 8-opioid receptors, suggesting the occurrence of physiological adverse interactions between the CCK and opioid systems in behavioural controLll56] Accordingly, the antidepressant -like effect of RB-lO 1, a mixed inhibitor of enkephalin-degrading enzymes which increases the levels of enkephalin in the brain, was potentiated by L-365,260 and suppressed by BC264. As expected, the facilitation induced by L-365,260 on RB-lOl responses was blocked by naltrindoleJl57]

An antidepressant-like effect was also elicited by L-365,260 in the forced-swimming test in mice. This could result from an increase of extracellular dopamine contents, since this effect was suppressed both by DI or D2 receptor-selective antagonists, while co-administration of nomifensine (a blocker of dopamine reuptake) with subthreshold doses of L-365,260 potentiated the effect of the drug alone.[158]



Taken together, these data suggest that the clinical use of CCKB antagonists could be extended to the treatment of depressive syndromes.[14oJ However, despite the positive data obtained in the mouse models of depression, the CCKB antagonist L-365,260 was ineffective in rat models (J. Harro, personal communication).

2.3 Schizophrenia

CCK is one of several neuropeptides possibly implicated in the pathophysiology of schizophrenia. The interest in the role of CCK in schizophrenia is mainly related to the following findings. First, CCK is co-localised with dopamine in the mesencephalic neurons.l 1031 Secondly, the highest levels of CCK and its receptors have been established in brain structures receiving dopaminergic innervation, including prefrontal cortex, striatum and limbic structures.[ 1591 In the nucleus accumbens of rats, CCK and dopamine interact at both pre- and postsynaptic levels.l159.1601 Numerous experiments have shown that CCK modulates the release of dopamine and that dopaminergic compounds modulate the release of CCK1161.1631 CCK has been found to both facilitate and inhibit dopaminergic activity.lI64.166]

The most prominent finding relevant to schizophrenia is a reduction of CCK activity in the cerebral cortex of patients with the disorder.l 167] This might be related to either altered processing of CCK in the cortical neurons, or loss of cortical neurons due to the schizophrenic process itself. Furthermore, repeated administration of the antipsychotic drug haloperidol has been shown to increase the density of CCK receptors in the mouse cerebral cortex.l 168] In contrast, long term methamphetamine administration, shown to cause a psychosis similar to paranoid schizophrenia or exacerbate schizophrenic symptoms, decreased the density of CCK binding sites in several cortical areas.l 169] Acute administration of CCK-8 produces an increase in dopamine D2 receptors in the striatum and mesolimbic structures, an effect similar to that of antipsychotic drugs.l l7OJ These data suggest that the major aim in schizophrenia should be to increase the function of


145

CCK rather than to block its effects by means of CCK antagonists.

2.3.7 Animal Models

Results from several experiments using rodents suggest that ceruletide and CCK have behavioural effects that resemble those of antipsychotic drugs.l' 71·1731 These nonselective CCK agonists have been shown to potently block the behavioural effects of several psychomotor stimulants including amphetamine, cocaine and methamphetamine.[I73] However, it should be noted that the antipsychotic-like effect of CCK agonists is significantly stronger in mouse models compared with studies performed in ratsJl 741 Moreover, in a study employing both rats and monkeys, the behavioural profile of the CCKA receptor agonist A68552 in conditioned avoidance tests did not resemble that of either haloperidol or clozapine.l l751

The CCKA antagonist devazepide, and the CCKB

antagonists L-365,260 and CI-988 did not modify the locomotor activity of rats after microinjection into the nucleus accumbens or ventral tegmental area; the locomotor effects of dopamine were also unaltered by the CCK antagonists.[S91 Moreover, the systemic administration ofL-365,260 and devazepide, in contrast to antipsychotic drugs (haloperidol, clozapine, raclopride), did not modify the intensity of apomorphine-induced aggressiveness in rats.l l761 However, CCK antagonists can potentiate certain behavioural effects of dopamine antagonists in rats. Csernansky et aJ.l 1771 found that pretreatment with proglumide potentiated the antagonist effects of haloperidol on apomorphine-induced stereotypies. Devazepide and L-365,260 also potentiated the rate-decreasing effects of the dopamine DI antagonist SKF-83566, and the dopamine D2 antagonist raclopride, under a fixed-ratio schedule. However, in a conditioned avoidance procedure, L-365,260 did not influence the effects of SKF-83566 and raclopride.l l7SJ

Many antipsychotic drugs decrease the number of spontaneously active dopamine cells in the substantia nigra and ventral tegmental area after long term administration, and most are known to produce catalepsy.[179,ISOl Electrophysiological studies in rats


146

demonstrated that short and long term administration of LY26269I , LY262684 and related pyrazolidin one CCKB antagonists decreased the number of spontaneously active dopamine cells in the substantia nigra zona compacta and ventral tegmental area, probably via an action at CCKB receptors in the striatum, nucleus accumbens and prefrontal cortex. [181-183] However, acute administration of these CCKB antagonists did not induce catalepsy in ratsJl82] Also, unlike the antipsychotic drugs haloperidol and clozapine, the CCKB antagonist LY288513 was not able to block amphetamine-induced hyperlocomotion (unpublished observations).

Therefore, the lack of effectiveness of CCKB antagonists against amphetamine-induced hyperlocomotion and apomorphine-induced aggressiveness do not add strength to the hypothesis, suggested by the electrophysiological studies, that CCKB antagonists may be potent antipsychotic drugs. However, the possibility still remains that CCKB antagonists can be used as an additional treatment to increase the effectiveness of conventional antipsychotics.

In contrast to the effects of CCKB antagonists in electrophysiological studies. the CCKA antagonists devazepide and lorglumide reversed the inhibitory effects of long term administration of haloperidol or clozapine on midbrain dopamine neuronsJI84-186] Furthermore, long term administration of lorglumide increased the number of spontaneously active ventral tegmental area dopamine cells, an effect opposite to that of long term, yet similar to short term, administration of antipsychotic drugS.[187] These data indicate that CCKA antagonists are not likely to be effective antipsychotics.

2.3.2 Human Studies There have been few reports that have directly

assessed the effects of CCK antagonists in patients with schizophrenia. Two clinical trials have examined the effect of the nonselective CCK antagonist proglumide in schizophrenia. Proglumide was added to an ongoing antipsychotic regimen in patients with refractory schizophrenia, but no improvement was observed. [1 88, 189] Moreover, treatment with the CCK analogue ceruletide did not have a beneficial


Shlik et al.

effect in 2 double-blind studies in which schizophrenic patients were not receiving antipsychotic medication. [190,191]

A reduction in CCK-like immunoreactivity was found in several brain regions at post-mortem in patients with schizophrenia.[l92-195] Reductions ofCCK binding sites have also been found in the hippocampus and frontal cortex. [1 96] Two other groups have noted that CCK levels in CSF were lower in patients with schizophrenia than in controlsJI48,150,197] Recently, the deficit of CCK mRNA was established in the frontal and temporal cerebral cortex in schizophreniaJ 167] The reduction of CCK-ergic activity is likely to reflect either a reduced processing of CCK in neurons, or the loss of neural cells due to the disease process of schizophrenia.

3. Conclusion

CCK is thought to be involved in the regulation of multiple CNS functionsJl59] However, to date most energy has been directed towards assessing the role of the peptide in the regulation of anxiety. The CCKB agonists CCK-4 and pentagastrin possess robust anxiogenic/panicogenic effects in humans, but the anxiolytic activity of CCKB antagonists remains to be demonstrated. The apparent contradictory properties of CCK agonists and antagonists can possibly be explained by: (i) the existence of 2 subtypes of CCKB receptors, which have different roles in the regulation of anxiety;D40-143] (ii) the interaction of CCK with various neurotransmitter systems (GABA, serotonin, noradrenaline, dopamine, glutamate, neuropeptide Y, nitric oxide) that are aetiologically involved in the expression of anxiety; and (iii) the low bioavailability of CCK receptor antagonists.

Many points need to be clarified to understand the role of CCK in psychopathology. First, the localisation of CCKB receptor subtypes in the various brain structures and in different animal species must be studied. Secondly, the development of CCKB receptor antagonists that are highly selective for these subtypes is desirable. Thirdly, the question of whether alternative splicing could be a possible source of subtypes of CCKB receptors must be answered.



Fourthly, the significance of polymorphism of the CCKB receptor gene needs to be further investigated in various anxiety disorders. Fifthly, studies need to investigate the interaction between CCK and the other neurotransmitter systems implicated in anxiety. At present, it is not clear whether the effects of CCK on anxiety are only mediated via other neurotransmitters, or whether CCK is directly involved in the neural networks responsible for anxiety. In addition, the possibility that CCK could mediate the effects of other neurotransmitters implicated in anxiety also needs to be investigated. Finally, another area of further study is the involvement of CCK in the mediation of anxiety caused by the abrupt discontinuation of various widely abused substances (benzodiazepines, alcohol, nicotine).

The role of CCK in depression and schizophrenia remains more obscure than the role of the peptide in anxiety disorders. Despite the positive data obtained from mouse models of depression, the CCKB antagonist L-365,260 is ineffective in rat models and no clinical data on the effect of this or other CCK antagonists are available. New CCKB

antagonists with better bioavailability (such as L-740,093) need to be tested in animal models of depression with the hope that they can be developed for assessment in humans.

The most prominent finding in schizophrenia is a reduction of CCK activity in the cerebral cortex. This might be related to either altered processing of CCK in the cortical neurons, or loss of cortical neurons due to the schizophrenic process itself. Therefore, the major aim for a CCK-based treatment for schizophrenia should be to increase the function of CCK rather than to block its effects by means of receptor antagonists.

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Correspondence and reprints: Dr Jacques Bradwejn, Psychobiology and Clinical Trials Research Unit, Clarke Institute of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario M5T IRS, Canada. E-mail: [email protected]


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Cholecystokinin and Psychiatric Disorders