cholecystokinin and Panic-Disorder

The classic gut hormone cholecystokinin (CCK) and its CCK

Topics: Adult; Cholecystokinin; Humans; Panic Disorder

Panic disorder (PD) is characterized by panic attacks, anticipatory anxiety and avoidance behavior. Its pathogenesis is complex and includes both neurobiological and psychological factors. With regard to neurobiological underpinnings, anxiety in humans seems to be mediated through a neuronal network, which involves several distinct brain regions, neuronal circuits and projections as well as neurotransmitters. A large body of evidence suggests that the neuropeptide cholecystokinin (CCK) might be an important modulator of this neuronal network. Key regions of the fear network, such as amygdala, hypothalamus, peraqueductal grey, or cortical regions seem to be connected by CCKergic pathways. CCK interacts with several anxiety-relevant neurotransmitters such as the serotonergic, GABA-ergic and noradrenergic system as well as with endocannabinoids, NPY and NPS. In humans, administration of CCK-4 reliably provokes panic attacks, which can be blocked by antipanic medication. Also, there is some support for a role of the CCK system in the genetic pathomechanism of PD with particularly strong evidence for the CCK gene itself and the CCK-2R (CCKBR) gene. Thus, it is hypothesized that genetic variants in the CCK system might contribute to the biological basis for the postulated CCK dysfunction in the fear network underlying PD. Taken together, a large body of evidence suggests a possible role for the neuropeptide CCK in PD with regard to neuroanatomical circuits, neurotransmitters and genetic factors. This review article proposes an extended hypothetical model for human PD, which integrates preclinical and clinical findings on CCK in addition to existing theories of the pathogenesis of PD.

Topics: Animals; Brain; Cholecystokinin; Humans; Mice; Nerve Net; Panic Disorder; Rats; Receptors, Cholecystokinin; Synaptic Transmission

Panic disorder is one of the chronic and disabling anxiety disorders. There has been evidence for either genetic heterogeneity or complex inheritance, with environmental factor interactions and multiple single genes, in panic disorder's etiology. Linkage studies have implicated several chromosomal regions, but no research has replicated evidence for major genes involved in panic disorder. Researchers have suggested several neurotransmitter systems are related to panic disorder. However, to date no candidate gene association studies have established specific loci. Recently, researchers have emphasized genome-wide association studies. Results of two genome-wide association studies on panic disorder failed to show significant associations. Evidence exists for differences regarding gender and ethnicity in panic disorder. Increasing evidence suggests genes underlying panic disorder overlap, transcending current diagnostic boundaries. In addition, an anxious temperament and anxiety-related personality traits may represent intermediate phenotypes that predispose to panic disorder. Future research should focus on broad phenotypes, defined by comorbidity or intermediate phenotypes. Genome-wide association studies in large samples, studies of gene-gene and gene-environment interactions, and pharmacogenetic studies are needed.

Topics: Catechol O-Methyltransferase; Cholecystokinin; Genetic Loci; Genome-Wide Association Study; Humans; Monoamine Oxidase; Panic Disorder

Cholecystokinin (CCK) peptides are involved in the control of multiple functions both in the central nervous system (CNS) and in the gastrointestinal tract where they act as neurotransmitters and regulate digestive functions. This review deals with the role of CCK peptides as vasoactive mediators. Recent work from our group demonstrates that CCK peptides induce neurogenic vasodilatation both in cerebral and mesenteric vessels. Such an effect is mediated by nitric oxide and seems to be presynaptic. These findings suggest that endogenous CCK peptides could be relevant vasodilatory agents involved in regulating both cerebral and splanchnic blood flow. We hypothesize here how such an effect could be useful in the interpretation of, in a new conceptual frame, the eventual contribution of CCK to some physiological and physiopathological events, such as splanchnic postprandial hyperaemia, panic attack or migraine.

Topics: Animals; Blood Vessels; Cerebrovascular Circulation; Cholecystokinin; Humans; Migraine Disorders; Models, Cardiovascular; Nitric Oxide; Panic Disorder; Receptors, Cholecystokinin; Splanchnic Circulation; Vasodilation

A bibliographic search has been performed in MEDLINE using cortisol and panic as key-words, occurring in the title and/or in the abstract. Human studies were selected, with no time limit. The following publications were excluded: review articles, case reports, panic attacks in disorders other than panic disorder, and studies on changes that occurred in-between panic attacks. The results showed that real-life panic attacks as well as those induced by selective panicogenic agents such as lactate and carbon dioxide do not activate the hypothalamic-pituitary-adrenal (HPA) axis. Agonists of the colecystokinin receptor B, such as the colecystokinin-4 peptide and pentagastrin, increase stress hormones regardless of the occurrence of a panic attack and thus, seem to activate the HPA axis directly. The benzodiazepine antagonist flumazenil does not increase stress hormones, but this agent does not reliably induce panic attacks. Pharmacological agents that increased anxiety in both normal subjects and panic patients raised stress hormone levels; among them are the alpha2-adrenergic antagonist yohimbine, the serotonergic agents 1-(m-chlorophenyl) piperazine (mCPP) and fenfluramine, as well as the psychostimulant agent caffeine. Therefore, the panic attack does not seem to activate the HPAaxis, in contrast to anticipatory anxiety.

Topics: Anxiety; Cholecystokinin; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Panic Disorder; Pituitary-Adrenal System

There is considerable evidence that genetic determinants play a major role in the etiology of anxiety. Investigations into susceptibility genes for anxiety are well underway, particularly for panic disorder and obsessive-compulsive disorder and more broadly defined anxiety-related traits, such as neuroticism and harm avoidance. This review will discuss some of the core issues related to diagnosis and molecular genetic methodology, followed by a review of recent molecular genetic findings for anxiety. The authors will attempt to highlight the numerous convergent and exciting findings. Given the rapid acceleration in knowledge of the human genome, a more definitive understanding of the genetic roots of these complex conditions may be anticipated in the relatively near future.

Topics: Anxiety Disorders; Brain-Derived Neurotrophic Factor; Catechol O-Methyltransferase; Child; Cholecystokinin; Gene Expression; Genetic Linkage; Glutamic Acid; Humans; Inhibition, Psychological; Membrane Glycoproteins; Membrane Transport Proteins; Molecular Biology; Nerve Tissue Proteins; Neurotic Disorders; Obsessive-Compulsive Disorder; Panic Disorder; Phenotype; Point Mutation; Serotonin; Serotonin Plasma Membrane Transport Proteins

Patients with premenstrual dysphoric disorder (PMDD) and patients with panic disorder (PD) both experience high rates of panic attacks in laboratory panic provocation studies. Recently, this shared elevated rate of challenge-induced panic has received increasing attention. Researchers have suggested that PMDD and panic disorder may share a pathophysiological or psychobiological link. The purpose of this paper is to review the findings from PMDD challenge studies and the theories advanced to connect PMDD to panic disorder. Taken together, the results of the PMDD challenge studies confirm that agents that incite panic in PD patients do so as well in PMDD women. This shared elevated challenge-induced panic cannot be accounted for by explanations such as a history of PD in PMDD women. None of the physiological theories as currently expressed--suffocation false alarm, gamma-aminobutyric acid (GABA), noradrenergic, serotonergic, and cholecystokinin--yet provides a compelling candidate to account for shared elevated challenge-induced panic in PD and PMDD patients. Psychological perspectives on panic emphasize that bodily sensations themselves can cause fear. Researchers have yet to apply several influential psychological approaches--conditioning, catastrophic misinterpretation, and anxiety sensitivity--to PMDD patients. Because psychological factors influence anxious responding in challenge studies, the search for the biological abnormality best accounting for PMDD panic might benefit from a reframing of the question to one that considers the psychological perspective as well.

Topics: Adult; Cholecystokinin; Fear; Female; Humans; Panic Disorder; Perception; Premenstrual Syndrome

The involvement of cholecystokinin (CCK) in human anxiety is well documented. Exogenous administration of CCK-2 receptor agonists, such as cholecystokinin-tetrapeptide and pentagastrin, provoke panic attacks in man. Patients with panic disorder (PD) are hypersensitive to CCK-2 receptor stimulation compared to healthy volunteers and patients with other anxiety disorders, and they differ from healthy subjects in CCK metabolism and genetic characteristics of the CCK-2 receptor system. This article reviews the corpus of work supporting the role of CCK in anxiety and suggests three research approaches which can further enhance our understanding of the CCK-2 system in PD. These approaches include: i) searching for a specific anomaly of the CCK-2 receptor system, ii) establishing a relationship between CCK-2 receptor polymorphism and vulnerability to pharmacologically-induced or spontaneous panic attacks, and iii) evaluating the therapeutic efficacy of CCK-2 receptor antagonists which possess adequate pharmacokinetic properties.

Topics: Cholecystokinin; Humans; Panic Disorder; Pentagastrin; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Research Design; Tetragastrin

The serendipitously discovered panicogenic effect of the cholecystokinin fragment, the C-terminal tetrapeptide amide (CCK-4), has suggested that the widespread network of CCK neurons and corresponding CCK-B receptors in the brain are in some way involved in pathogenesis panic disorders in man. Two decades of research have now established that exogenous CCK-4 in a reproducible, dose-dependent and sensitive manner indeed evokes panic attacks in both healthy subjects and at even lower doses in anxiety patients. But several questions about the molecular mechanisms by which endogenous CCK peptides may precipitate panic attacks remain to be answered. This review focuses on three immediate questions. (1) Does endogenous CCK-4 exist? (2) Is the panicogenic effect mediated only through CCK-B receptors? (3) Are measurements of CCK peptides in cerebrospinal fluid of use in elucidating the pathogenesis and/or diagnosis? This review concludes that the answers to these questions may further the understanding of panic disorder substantially, and hence contribute to improved diagnosis and therapy of the disease.

Topics: Amino Acid Sequence; Animals; Cholecystokinin; Humans; Molecular Sequence Data; Panic Disorder; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Tetragastrin

Although Social Phobia has been recognised for centuries in comparison with other anxiety disorders, relatively little work has been done to understand its neural basis. The present review attempts to redress this balance by giving an overview of the current state of knowledge in this disorder. By putting together data from the treatment responses to specific agents, the effects of chemical challenges which have been used in other anxiety disorders and by reviewing data on central and peripheral neurotransmitter and endochrine abnormalities, it is possible to begin to generate some potentially testable theories of aetiology and mechanisms. Finally, we review the potential use of neuroimaging techniques to better detail the brain circuits and possibly neurotransmitters involved in social phobia, showing some of our preliminary work using (15)O water blood flow PET activation studies to determine the brain circuits in which metabolism is changed during the experience of social anxiety.

Topics: Brain; Caffeine; Carbon Dioxide; Cholecystokinin; Epinephrine; Female; Flumazenil; Human Growth Hormone; Humans; Hypothalamo-Hypophyseal System; Lactic Acid; Male; Neurotransmitter Agents; Panic Disorder; Phobic Disorders; Pituitary-Adrenal System; Thyroid Gland; Tomography, Emission-Computed; Tomography, Emission-Computed, Single-Photon

A study on the biology of 'panic disorder,' which I have classified under the category of 'anxiety disorder,' made progress recently. In a genetic study, the hereditary of panic disorder was checked by a 'linkage and twins' study, and the anticipation of panic disorder was recognized as being the same as that which is also found in the psychiatric conditions known as schizophrenia and manic depression. A panic disorder patient regards the anxious sign of a model as ruinous, and this weakness in recognition has been duly noted. Therefore, I studied a patient showing a continuance state of 'hyper-sensitivity,' and compared this to a patient showing a 'sleep disorder.' Noradrenaline plays an important role in anxiety as suppression of the locus ceruleus (LN), the major NE-containing nucleus of the noradrenaline nervous system, brings on a calming effect. Yohimbine, however, which is an alpha 2 antagonist, is found to induce panic attacks. The fact that selective serotonin reuptake inhibitor (SSRI) suppresses panic attacks suggests that serotonin is connected with panic disorders. It is also thought that the 'raphe nucleus' is the site of origin of the serotonin nervous system, which participates in the control of anxiety. This suggests the participation of a gamma-aminobutyric acid (GABA) nervous system in which the administration of benzodiazepine at a high potency would be an effective agent against panic disorder. Cholecystokinin (CCK) is also suggested to have a connection with panic disorder as CCK-4 causes panic attacks. There has been no CCK antagonist found effective for an object- or time-oriented panic disorder at the present. It is thought that corticotropin-releasing factor (CRF) is released during a panic attack. The development of a new CRF receptor antagonist is needed. In addition to the studies on the neurotransmitters of the traditional type, such as noradrenaline, serotonin and GABA, studies on the neuropeptides, such as CCK and CRF have become important for future consideration. Understanding this, image studies such as MRI, SPECT, fMRI and PET have become highly desirable.

Topics: Cholecystokinin; Corticotropin-Releasing Hormone; Diagnostic Imaging; gamma-Aminobutyric Acid; Humans; Neuropeptides; Neurotransmitter Agents; Norepinephrine; Panic Disorder; Serotonin

Various provocative agents, including sodium lactate, carbon dioxide (CO2), caffeine, yohimbine, serotoninergic agents, and cholecystokinin (CCK), have been utilized as panicogenics in studies on healthy volunteers as well as in panic disorder patients. An overview of the utilization of these agents to study the neurobiology of panic disorder is presented. The possible roles of several neurotransmitters and neuromodulators in the etiology of panic disorder and in the actions of drugs used in its treatment are also discussed.

Topics: Caffeine; Carbon Dioxide; Cholecystokinin; Humans; Neurotransmitter Agents; Panic Disorder; Piperazines; Serotonin Receptor Agonists; Sodium Lactate; Synaptic Transmission; Yohimbine

Extensive studies were carried out on the involvement of the CCKergic system in anxiety-, panic- and stress-related behaviour. The stimulation of CCK-A or CCK-B receptors is implicated in the physical and psychological responses of CCK to stress. Furthermore, several selective CCK-B agonists produce anxiogenic-like effects, while CCK-B antagonists induce anxiolytic-like responses in several models of anxiety. However, BC264 a highly selective CCK-B agonist, does not produce anxiogenic-like effects but increases attention and/or memory. These effects are dependent on the dopaminergic systems. Together with biochemical data, this led to the hypothesis of the existence of two CCK-B binding sites, CCK-B1 and CCK-B2, which could correspond to different activation states of a single molecular entity. Investigations into CCK-B1 and CCK-B2 systems might be of critical interest, since only one site, CCK-B1, appears to be responsible for the effects of anxiety. Furthermore, the improvement of attention and/or memory processes by CCK, through CCK-B2 receptors, could offer a new perspective in the treatment of attention and/or memory disorders.

Topics: Animals; Anxiety; Cholecystokinin; Cognition; Humans; Panic Disorder; Receptor, Cholecystokinin B; Receptors, Cholecystokinin

The neurobiology of social anxiety disorder is poorly understood, although preliminary research has suggested several possible biological abnormalities. Challenge studies have demonstrated that subjects with social anxiety disorder have a sensitivity to carbon dioxide, cholecystokinin, and caffeine somewhere between that of panic disorder patients and normal controls. Serotonergic pathways may play a role in social anxiety disorder, as shown by the clinical effectiveness of selective serotonin reuptake inhibitors, plus fenfluramine and m-chlorophenylpiperazine challenge studies. Dopaminergic function and striatal dopamine uptake appear to be reduced in social anxiety disorder. There is also evidence for cardiovascular and adrenergic abnormalities. Recently, positron emission tomography has begun to identify brain regions that appear to be uniquely activated in this condition. These results offer the promise of an understanding of the brain mechanisms of social anxiety disorder, but much further research is needed to fully elucidate the neurobiological cause(s) that exist.

Topics: Animals; Brain; Caffeine; Carbon Dioxide; Cholecystokinin; Dopamine; Fear; Fenfluramine; Humans; Panic Disorder; Paroxetine; Phobic Disorders; Piperazines; Rats; Ritanserin; Selective Serotonin Reuptake Inhibitors; Serotonin; Tomography, Emission-Computed

Various provocative agents, including sodium lactate, carbon dioxide (CO2), caffeine, yohimbine and cholecystokinin (CCK), have been utilized as panicogenics in studies on healthy volunteers as well as in panic disorder patients. Most provocative agents are lacking in specificity, limiting their use in identifying neurotransmitter systems involved in panic attacks. CCK appears to offer several advantages over other challenge strategies since it is a putative neurotransmitter in the CNS, with its own neuronal pathways and receptors, and reliably provokes panic attacks in a dose-dependent manner. It is important to clarify the relationships between CCK and other neurotransmitter systems in order to further understand the neurobiology of panic disorder. The possible roles of some of these neurotransmitters in panic disorder are discussed in this review.

Topics: Arousal; Brain; Caffeine; Carbon Dioxide; Cholecystokinin; Humans; Lactic Acid; Neurotransmitter Agents; Panic; Panic Disorder; Yohimbine

Advances over the past 2 decades in our understanding of the biology of panic disorder have paralleled a remarkable increase in the development of new pharmacological agents with antipanic effects. Although we can not presently use biological tests to help with our choice of therapeutic agent for individual patients, we can use this biological understanding in the development of overall pharmaco-therapeutic strategies. Current evidence does not support the hypothesis that panic disorder is associated with a primary disorder in one neurotransmitter system. Rather, the data suggest that the biological aetiology of panic disorder is related to abnormalities in the function of a variety of neurotransmitters including serotonin (5-hydroxytyrptamine; 5-HT), noradrenaline (norepinephrine), gamma-aminobutyric acid (GABA), dopamine, and cholecystokinin. It is likely, however, that panic disorder is a biologically heterogeneous condition and that biological subtypes may exist in which the primary abnormality may involve one or a few neurotransmitter systems. Currently, the data best support the hypothesis that pharmacotherapeutic agents with primary action at sites within the GABA and serotonin systems are the most effective in the treatment of panic disorder. Nevertheless, some patients will respond well to drugs with predominant activity in other systems, or may require pharmacotherapy designed to affect the function of more than 1 neurotransmitter. As our understanding of the biological aetiology of panic disorder evolves, the pharmacotherapeutic agents and strategies used in the treatment of this disorder will continue to evolve as well.

Topics: Benzodiazepines; Cholecystokinin; Cognitive Behavioral Therapy; Dopamine; gamma-Aminobutyric Acid; Humans; Norepinephrine; Panic Disorder; Selective Serotonin Reuptake Inhibitors; Serotonin; Synaptic Transmission

Interest in the biological aspects of panic disorder has been focussed mainly on the noradrenergic and serotonergic systems in the brain. Recently evidence has been found that Cholecystokinin (CCK) receptors in the Central Nervous System (CNS) may be involved in panic disorders. This hypothesis is based on the results of animal electrophysiological studies, animal models of anxiety and on challenge test using CCK fragments in humans. In this review, the studies evaluating the putative involvement of CCK, and especially CCK-B receptors, in panic disorder will be discussed.

Topics: Animals; Behavior, Animal; Cholecystokinin; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Panic Disorder; Rats; Receptors, Cholecystokinin

Topics: Animals; Anxiety; Anxiety Disorders; Cholecystokinin; Humans; Panic Disorder; Receptors, Cholecystokinin; Tetragastrin

Cholecystokinin (CCK) is a neurotransmitter found in high density in the brains of mammals. Microiontophoretic studies showing that benzodiazepines selectively antagonized CCK-induced excitation of rat hippocampal neurons have led to the hypothesis that CCK is an anxiogenic peptide. The hypothesis was supported by demonstrations that CCK-tetrapeptide (CCK4) induces panic attacks in humans. This paper reviews phases of investigations which studied the validity of CCK4 as a panicogenic agent and research strategies for the study of panic disorder using CCK4 as an investigative tool.

Topics: Amino Acid Sequence; Base Sequence; Benzodiazepines; Brain; Cerebrovascular Circulation; Cholecystokinin; Female; Hippocampus; Humans; Imipramine; Male; Molecular Sequence Data; Neurotransmitter Agents; Panic Disorder; Sincalide; Tetragastrin

Topics: Anxiety Disorders; Benzodiazepinones; Cholecystokinin; Devazepide; Humans; Panic Disorder; Pentagastrin; Receptors, Cholecystokinin

Pentagastrin is a cholecystokinin (CCK)-B agonist and laboratory panicogenic agent that produces endocrine (ACTH and cortisol), symptom (anxiety, panic) and cardiovascular (heart rate) responses. Although in vitro data have supported its chemical stability, preliminary data suggested that increasing time between drug preparation and drug infusion could reduce the magnitude of endocrine and symptom responses. The current study examined this possibility. Twenty-one healthy subjects presented at the University of Michigan General Clinical Research Center (GCRC) and had an intravenous catheter inserted. Heart rate, cortisol levels and subjective anxiety were measured before and after pentagastrin and placebo injections. Pentagastrin was prepared either within 60 min of IV infusion (Normal Preparation group) or at least 3.5 h prior to infusion (Early Preparation group). Relative to the Normal Preparation group, Early Preparation subjects had similar heart rate responses but significantly smaller cortisol and subjective anxiety responses. Early preparation of pentagastrin thus appears to weaken endocrine and subjective anxiety responses, highlighting the importance of attending to often overlooked procedural variables (e.g., time between preparation and administration) in studies of this type. The sensitivity of cortisol and anxiety responses to preparation time, but insensitivity of heart rate, is consistent with previous studies suggesting different thresholds of activation for the three response modalities. These differential sensitivities may suggest different and separable CCK-B stimulated pathways for each response, which combine to produce panic, rather than a single, unified CCK-B mediated panicogenic response.

Topics: Adult; Anxiety; Cholecystokinin; Drug Administration Schedule; Female; Gastrointestinal Agents; Heart Rate; Humans; Hydrocortisone; Infusions, Intravenous; Male; Panic Disorder; Pentagastrin; Time Factors

This study investigated the effects of continuous slow infusion of cholecystokinin tetrapeptide (CCK-4), a neuropeptide with panicogenic properties, on functional hemispheric differences, as indexed by quantitative electroencephalographic (EEG) asymmetry and coherence measures. Twenty-four adult volunteers (15 females and 9 males) were assigned to infusion with either placebo or CCK-4 in a randomized, double-blind, parallel-group design, with EEG being recorded before and during (10 and 40 min) a 60-min infusion period. No significant treatment differences were observed for absolute EEG power but, compared to placebo, CCK-4 infusion increased asymmetry and reduced coherence of slow-wave activity at midtemporal recording sites. These findings support the contention that functional imbalance of the temporal cortex, perhaps mediated by CCK-4, is involved in panic disorder (PD).

Topics: Adolescent; Adult; Cholecystokinin; Double-Blind Method; Electroencephalography; Female; Functional Laterality; Humans; Infusions, Intravenous; Male; Panic Disorder; Placebos; Temporal Lobe

This study examined the effects of i.v. administration of cholecystokinin-tetrapeptide (CCK-4) on plasma release of arginine vasopressin (AVP) and oxytocin (OT) in women with premenstrual dysphoric disorder (PMDD) and control women, during both the follicular phase and the luteal phase of their menstrual cycle. Plasma AVP and OT concentrations increased following CCK-4 administration. AVP and OT response to CCK-4 was similar for PMDD and control women and unaffected by menstrual cycle phase. AVP and OT may play a role in the hypothalamo-pituitary adrenal (HPA) axis activity associated with the panic response induced by CCK-4.

Topics: Adult; Arginine Vasopressin; Cholecystokinin; Cross-Over Studies; Double-Blind Method; Female; Humans; Oxytocin; Panic Disorder; Peptides; Placebos; Premenstrual Syndrome; Radioimmunoassay; Tetragastrin; Time Factors; Vasoconstrictor Agents

To gain insight into whether ondansetron treatment induces changes in total cholecystokinin (CCKT) plasma levels before and after administration of the cholecystokinin tetrapeptide (CCK-4) panic challenge procedure in healthy men.. Thirty-eight volunteers received a 50-microgram bolus of CCK-4 60 minutes after a single oral dose (acute treatment) and multiple oral doses (chronic treatment) of ondansetron or placebo.. Results showed no difference in CCKT plasma levels of CCKT elimination rate constant between the ondansetron and the placebo groups after either acute or chronic treatment.. Results from this study suggest that total CCK plasma levels are not influenced by either acute or chronic treatment with ondansetron. However, the effect of ondansetron on the different CCK component fractions still needs exploration.

Topics: Administration, Oral; Adolescent; Adult; Anti-Anxiety Agents; Cholecystokinin; Double-Blind Method; Humans; Male; Middle Aged; Ondansetron; Panic Disorder; Tetragastrin

The anxiogenic and panicogenic effects of peripheral administration of the cholecystokinin-B receptor agonist pentagastrin and placebo were evaluated in patients with generalized anxiety disorder and normal comparison subjects.. Seven patients with generalized anxiety disorder and seven age- and sex-matched normal subjects received an intravenous bolus of placebo and pentagastrin.. Panic attacks occurred in five patients with generalized anxiety disorder (71%) and in one normal subject (14%). Patients with generalized anxiety disorder were more likely to report more nonpanic anxiety than were normal subjects.. Patients with generalized anxiety disorder appear to exhibit greater subjective sensitivity to pentagastrin than do normal subjects.

Topics: Anxiety Disorders; Cholecystokinin; Humans; Infusions, Intravenous; Panic Disorder; Pentagastrin; Pilot Projects; Placebos

Eight patients with panic disorder were administered 20 micrograms of cholecystokinin tetrapeptide (CCK-4) before and after 8 weeks of treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram. All patients responded to treatment by showing a significant general improvement and reaching a panic-free state for 2 weeks. At the rechallenge with CCK-4, patients displayed a marked reduction in the intensity and number of panic symptoms. The frequency of panic attacks induced with CCK-4 decreased by 50% after treatment. Citalopram treatment had no substantial effect on cardiovascular (heart rate and blood pressure) or hormonal (cortisol, prolactin and growth hormone) responses to CCK-4. Patients who still had panic attacks after treatment demonstrated a blunted growth hormone response to CCK-4 that was not seen in those who did not have panic attacks. This study suggests that treatment with an SSRI can reduce an enhanced sensitivity to CCK-4 without modifying cardiovascular and neuroendocrine responses to CCK-4 in patients with panic disorder.

Topics: Adolescent; Adult; Behavior; Cholecystokinin; Citalopram; Female; Hemodynamics; Humans; Male; Neurosecretory Systems; Panic Disorder; Psychiatric Status Rating Scales; Selective Serotonin Reuptake Inhibitors

The effects of pentagastrin, a synthetic analogue of the cholecystokinin tetrapeptide (CCK4), were studied in 15 patients with panic disorder and 15 healthy controls. Three different intravenous dosages of pentagastrin (0.1, 0.3 and 0.6 microgram/kg) and saline were investigated. Subjects were randomly allocated to two of the four treatment groups and tested on two separate occasions, 1 week apart, using an unbalanced double-blind incomplete block design. The mean panic rate with pentagastrin was 55% (12/22) for patients and 5% (1/22) for controls. None of the subjects panicked with saline. The frequency of panic attacks between the three pentagastrin doses in patients was not different. One control subject had a panic-like attack at the highest dose of pentagastrin. These findings concur with previous studies on the panicogenic effect of CCK4 and pentagastrin and suggest a greater sensitivity for CCK receptor agonists in patients suffering from panic disorder than in healthy controls.

Topics: Adult; beta-Endorphin; Cholecystokinin; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Hydrocortisone; Melatonin; Methoxyhydroxyphenylglycol; Middle Aged; Norepinephrine; Panic Disorder; Pentagastrin; Prolactin; Psychiatric Status Rating Scales; Psychometrics; Serotonin

Cholecystokinin (CCK) may mediate human anxiety and animal data suggest that cholecystokinin antagonists could provide an important advance in the treatment of anxiety disorders. The study of CCK receptor systems in psychiatric patients has, however, been severely limited by the lack of available probes. We utilized intravenous infusions of pentagastrin, a selective CCK-B receptor agonist, and studied behavioral and cardiovascular responses in 10 patients with panic disorder and 10 normal controls. Pentagastrin produced substantial symptomatology, including anxiety, and increases in heart rate and blood pressure, in both patients and controls. Patients were more sensitive to the panicogenic effects of the pentagastrin. Panic attacks occurred in 70% of patients and 0% of controls. Patients' symptom responses were very similar to their "typical" panic attacks and to symptoms produced by CCK4. Pentagastrin provides a readily available alternative to CCK4 for studying the CCK receptor system and exploring its involvement in human anxiety.

Topics: Adult; Agoraphobia; Arousal; Blood Pressure; Cholecystokinin; Female; Heart Rate; Humans; Male; Norepinephrine; Panic; Panic Disorder; Pentagastrin; Receptors, Cholecystokinin; Single-Blind Method; Tetragastrin

Anxiety disorders including panic disorder (PD) are the most prevalent psychiatric diseases leading to high disability and burden in the general population. Acute panic attacks are distinctive for PD but also frequent in other anxiety disorders. The neurobiology or specific molecular changes leading to and present during panic attacks are insufficiently known so far.. In the present pilot study, we investigated dynamic metabolomic and gene expression changes in peripheral blood of patients with PD (n = 25) during two exposure-induced acute panic attacks.. The results show that the metabolite glyoxylate was dynamically regulated in peripheral blood. Additionally, glyoxylate levels were associated with basal anxiety levels and showed gender-related differences at baseline. As glyoxylate is part of the degradation circuit of cholecystokinin, this suggests that this neuropeptide might be directly involved in exposure-induced panic attacks. Only gene expression changes of very small magnitude were observed in this experimental setting.. From this first metabolome and gene expression study in exposure-induced acute panic attacks in PD we conclude that metabolites can potentially serve as dynamic markers for different anxiety states. However, these findings have to be replicated in cohorts with greater sample sizes.

Topics: Adult; Anxiety; Cholecystokinin; Female; Gene Expression Regulation; Glyoxylates; Humans; Male; Metabolome; Panic Disorder; Pilot Projects; Prevalence; Sex Characteristics

Cholecystokinin (CCK) is a neuropeptide that has been implicated in understanding the acquisition and extinction of fear. Research on CCK in anxiety has primarily focused on understanding panic attacks and panic disorder. Emerging data suggests that CCK may also hold promise in understanding the development and maintenance of posttraumatic stress disorder (PTSD).. The present study examined whether a single nucleotide polymorphism in the promoter region of the CCK gene (C>T; rs1799923) was associated with an increased prevalence of PTSD as well as with severity of PTSD symptoms among a sample of 457 combat veterans.. Results demonstrated that participants with either the heterozygous or homozygous T allele had an increased prevalence of PTSD relative to participants with the CC genotype (OR=2.17; 95% CI [1.37-3.43]).. The relatively small sample size precluded examination of racial/ethnic differences. Findings were also limited by the absence of a systematic assessment of comorbid anxiety psychopathology.. These data offer preliminary evidence supporting an association between the rs1799923 polymorphism in the CCK gene and PTSD. Additional research is needed to better understand the nature of this relationship.

Topics: Adult; Alleles; Anxiety Disorders; Cholecystokinin; Combat Disorders; Female; Genotype; Humans; Male; Middle Aged; Panic Disorder; Polymorphism, Genetic; Promoter Regions, Genetic; Stress Disorders, Post-Traumatic; Veterans

The cholecystokinin (CCK) system has long been hypothesised to have a role in the pathogenesis of panic attacks. Previous research into genetic variation within the CCK gene and the genes for its two receptors, CCKAR and CCKBR, has produced mixed results. We aimed to clarify this association by investigating multiple variants within each gene and multiple phenotypes associated with panic that may have confounded the previous studies' findings.. Variants were selected for the three genes based on HapMap CEU data. Individuals from a family based cohort (n=563) were genotyped for these variations and this data was analysed in FBAT.. CCKBR showed the strongest association with panic, having multiple variants with p<0.05 (lowest: p=0.007). In CCKAR, some evidence was found for an association with panic, though further analysis suggested that the co-morbid bipolar-panic phenotype was most strongly associated. No variants in CCK were associated with panic but broader anxiety phenotypes did show associations.. Small sample size prevented thorough investigation of phenotypes, particularly pure disorders, and no correction was made for the multiple phenotypes analysed.. Our findings support the involvement of variation in the CCK system, particularly CCKBR, in the pathogenesis of panic. Our data suggest that variation in CCK may be involved in several anxiety phenotypes and CCKAR may be involved in the development of panic co-morbid with bipolar disorder. These latter findings require further investigation and highlight the importance of clearly defined phenotypes when investigating psychiatric genetics.

Topics: Adolescent; Adult; Cholecystokinin; Cohort Studies; Comorbidity; Humans; Mood Disorders; Panic Disorder; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Young Adult

Panic disorder (PD) is a common psychiatric disease occurring more frequently in women than men. Multiple common and/or rare variants in the genome contribute to the complex etiology of the disorder. The neuropeptide cholecystokinin (CCK) and its receptors (the CCK system) have been suggested to be involved in the pathogenesis of PD.. We examined the promoter, exon, and exon-intron boundaries of the genes encoding CCK and its receptors (CCKAR and CCKBR) for variations in 187 patients with PD and 277 screened control individuals. Up to 1342 additional healthy population controls were examined for some of the variations. One CCK gene intron variation was analyzed for alternative splicing using an exon-trapping assay.. The promoter variant (-36C > T; rs1799923) and an intron 1 polymorphism (IVS1-7C > G; rs754635) in the CCK gene were found to protect against PD (P<0.05). The intron 1 variation did not seem to alter the splicing of the gene. None of the other variations found were associated with PD, but a 2-marker haplotype (rs1800855/rs1800857) in the CCKAR gene protected women against PD (P=0.004). In addition, we found two novel rare missense variations in the CCKBR gene (Lys329Asn and Pro446Leu) in two and one patient, respectively.. The results suggest that the CCK system may play a role in the pathogenesis of PD, with susceptibility alleles both protecting and contributing to the disease. Both common and rare variants seem to be involved. The involvement of the CCK system may also contribute to the increased prevalence of PD in women.

Topics: Alternative Splicing; Cholecystokinin; Exons; Female; Genetic Variation; Humans; Introns; Male; Panic Disorder; Promoter Regions, Genetic; Receptors, Cholecystokinin

Eating disorders (EDs) have a highly heterogeneous etiology and multiple genetic factors might contribute to their pathogenesis. Ghrelin, a novel growth hormone-releasing peptide, enhances appetite and increases food intake, and human ghrelin plasma levels are inversely correlated with body mass index. In the present study, we examined the 171T/C polymorphism of the ghrelin receptor (growth hormone secretagogue receptor, GHSR) gene in patients diagnosed with EDs, because the subjects having ghrelin gene polymorphism (Leu72Met) was not detected in a Japanese population, previously. In addition, beta3 adrenergic receptor gene polymorphism (Try64Arg) and cholecystokinin (CCK)-A receptor (R) gene polymorphism (-81A/G, -128G/T), which are both associated with obesity, were investigated. The subjects consisted of 228 Japanese patients with EDs [96 anorexia nervosa (AN), 116 bulimia nervosa (BN) and 16 not otherwise specified (NOS)]. The age- and gender-matched control group consisted of 284 unrelated Japanese subjects. The frequency of the CC type of the GHSR gene was significantly higher in BN subjects than in control subjects (chi(2) = 4.47, p = 0.035, odds ratio = 2.05, Bonferroni correction: p = 0.070), while the frequency in AN subjects was not different from that in controls. The distribution of neither beta3 adrenergic receptor gene nor CCK-AR polymorphism differed between EDs and control subjects. Therefore, the CC type of GHSR gene polymorphism (171T/C) is a risk factor for BN, but not for AN.

Topics: Adult; Aged; Body Mass Index; Bulimia Nervosa; Cholecystokinin; DNA; Feeding and Eating Disorders; Female; Genotype; Humans; Japan; Male; Middle Aged; Panic Disorder; Polymorphism, Single Nucleotide; Receptors, Adrenergic, beta-3; Receptors, Cholecystokinin; Receptors, G-Protein-Coupled; Receptors, Ghrelin; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors

In the present investigation we screened a large number of single nucleotide polymorphisms in the genes relevant to the neurobiology of anxiety for their association with panic disorder (PD).. The study sample included 127 patients with PD and 146 healthy control subjects. Using Arrayed Primer Extension technology we genotyped 90 polymorphisms in 21 candidate genes of serotonin, cholecystokinin, dopamine and opioid neurotransmitter systems. The association and haplotype analyses were performed in the whole group (PD-all) and in the subgroups of PD comorbid with major depression (PD-comorbid, n = 60) and without any comorbidity (PD-pure, n = 42).. From the set of 90 polymorphisms, eight single nucleotide polymorphism markers in eight genes displayed at least a nominal association with any of the studied PD phenotype subgroups. Several polymorphisms of cholecystokinin, serotonin and dopamine systems were associated with PD-all and/or PD-comorbid phenotypes, while pure PD was associated only with HTR2A receptor 102T-C (P = 0.01) and DRD1 receptor -94G-A (P = 0.02) polymorphisms. Haplotype analysis supported an association of the cholecystokinin gene TG haplotype with the PD-all group (P = 0.04), whereas DRD1 receptor CAA and HTR2A receptor AT haplotypes were associated with a lower risk for PD-pure phenotype (P = 0.03 and P = 0.04, respectively).. The study results suggest that genetic variants of several candidate genes of neurotransmitter systems, each of a minor individual effect, may contribute to the susceptibility to PD. Our data also indicate that genetic variability may have a distinctive influence on pure and comorbid phenotypes of PD.

Topics: Cholecystokinin; Comorbidity; Depressive Disorder; DNA; DNA Primers; Genotype; Humans; Oligonucleotide Array Sequence Analysis; Panic Disorder; Polymorphism, Genetic; Receptors, Dopamine; Receptors, Serotonin; Reference Values

Cholecystokinin (CCK) has been implicated in anxiety disorders. The midbrain periaqueductal gray (PAG), which modulates anxiety and panic reactions, contains CCK-immunoreactive fibers and CCK(2) receptors. The present study investigated the involvement of CCK(2) receptors of the PAG dorsolateral subdivision (dlPAG) in the regulation of inhibitory avoidance and escape, two defensive behaviors that have been related in terms of psychopathology to generalized-anxiety and panic disorders, respectively. Male Wistar rats were microinjected in the dlPAG with the CCK(2) receptor agonist cholecystokinin-tetrapeptide (CCK-4; 0.08-0.32 nmol/0.2 microL), the CCK(2) receptor antagonist LY-225910 (0.05-0.20 nmol/0.2 microL) or LY-225910 prior to CCK-4. Inhibitory avoidance and escape behaviors were evaluated in the elevated T-maze. Whereas CCK-4 facilitated escape, indicating a panic-like action, LY-225910 had the opposite effect. Pretreatment with a non-effective dose of LY-225910 prevented the panic-eliciting action of CCK-4. Neither CCK-4 nor LY-225910 affected inhibitory avoidance acquisition. The present results substantiate the view that dlPAG CCK(2) receptors modulate panic-related behaviors.

Topics: Animals; Avoidance Learning; Behavior, Animal; Cholecystokinin; Disease Models, Animal; Exploratory Behavior; Fear; Male; Maze Learning; Motor Activity; Neural Pathways; Panic Disorder; Periaqueductal Gray; Quinazolines; Quinazolinones; Rats; Rats, Wistar; Receptor, Cholecystokinin B; Tetragastrin

Panic disorder like other neuropsychiatric disorders is believed to be caused by multiple psychosocial and biological factors. Several lines of evidence point to a role for the peptide neurotransmitter cholecystokinin in the pathogenesis of panic disorder. We therefore determined the allele and genotype frequencies of a single nucleotide polymorphism in the CCK gene (-36C>T) and one CT repeat polymorphism in the CCK-B-receptor gene in a German panic disorder sample (n = 115 for CCK gene polymorphism, n = 111 for CCK-B-receptor polymorphism) and compared them with gender and age matched controls. The length of the polymorphic CT repeat alleles varies between 146 bp and 180 bp. We first analysed the results by a permutation test which provided evidence for heterogeneity between patients and controls (p=0.002). We then analysed the data as a di-allelic polymorphism with a short (146-162bp) and a long (164-180bp) allele and as a tetra-allelic polymorphism with 4 alleles (146-154bp, 156-162bp, 164-170bp, 172-180bp). In the di-allelic analysis as well as in the tetra-allelic analysis there was an excess of the longer allele (p = 0.001) or the two longer alleles (p = 0.041) respectively in patients with panic disorder. No difference between groups was observed for the -36C > T polymorphism. Our findings are consistent with the notion that genetic variation in the CCK neurotransmitter system contributes to the pathogenesis of panic disorder.

Topics: Adult; Cholecystokinin; Confidence Intervals; Female; Gene Frequency; Genetic Variation; Genotype; Humans; Male; Middle Aged; Odds Ratio; Panic Disorder; Polymorphism, Genetic; Receptor, Cholecystokinin B

The authors report that cholecystokinin (CCK), via its subtype 2 receptor (CCK2R) located presynaptically on cerebral arteries, mediates the release of nitric oxide (NO), which induces vasodilatation. Whereas CCK octapeptide and its fragment CCK tetrapeptide (CCK-4) lack a direct effect on the smooth muscle of pial vessels, the authors showed that both CCK peptides modulate the neurogenic responses in bovine cerebral arteries. The neurogenic vasodilatation induced by CCK-4 was blocked by the CCK2R antagonist, L-365,260, and antagonized by neuronal NO synthase (nNOS) inhibitors, but was independent of the endothelium. In whole-mount arteries, CCK2Rs were detected in nerve fibers and colocalized with nNOS and synaptophysin. The findings provide, for the first time, a neural mechanism by which CCK may increase cerebral blood flow.

Topics: Animals; Cattle; Cerebral Arteries; Cholecystokinin; In Vitro Techniques; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Panic Disorder; Pia Mater; Presynaptic Terminals; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Sincalide; Tetragastrin; Tissue Distribution; Vasodilation

We previously identified a polymorphic compound short tandem repeat (STR) in the 5'-regulatory region of the cholecystokinin (CCK) gene, and showed that when the STRs were classified into three groups based on length and linkage disequilibrium behavior with neighboring variants, the medium class allele was significantly associated with panic disorder. The present study examined the transcriptional activity of the CCK promoter construct containing the STR and downstream -188A/G variation. The STRs acted as transcriptional repressors with a similar potency among the three classes, but the long (L) class STR exhibited a synergistic effect on decreasing promoter activity when combined with -188G. The haplotype composed of the L class of STR and -188G was significantly less frequent in panic disorder (P = 0.0032; odds ratio, 95% confidence interval = 0.06, 0.01-0.69). These results suggest that the L-(-188G) haplotype may act as a protective factor against panic by reducing the expression of anxiogenic CCK.

Topics: Alleles; Cholecystokinin; Gene Frequency; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Luciferases; Panic Disorder; Promoter Regions, Genetic; Recombinant Fusion Proteins; Tandem Repeat Sequences; Transcriptional Activation; Transfection; Tumor Cells, Cultured

Growing animal data implicate cholecystokinin in the regulation of anxiety, while human clinical research confirms the role of cholecystokinin in the provocation of panic attacks. Antipanic medications suppress the ability of cholecystokinin to induce panic attacks, and may alter the expression of the cholecystokinin gene. Thus, there is increased interest in understanding the molecular genetic component of these observations. Recent association studies using persons with panic disorder described some association between polymorphisms in the genes encoding cholecystokinin and the cholecystokinin B-receptor and panic disorder. In this study, we used a family-based design, employing 596 individuals in 70 panic disorder pedigrees, as well as 77 haplotype relative risk 'triads'. Subjects were genotyped for two polymorphisms: the polymorphic microsatellite marker in the CCK-BR locus using PCR-based genotyping and at a single nucleotide polymorphism in the CCK promoter using a fluorescence polarization detection assay, and the data were analyzed for genetic association and linkage. Employing a variety of diagnostic and genetic models, linkage analysis produced no significant lod scores at either locus. Family-based tests of association, the haplotype-based haplotype relative risk statistic and the transmission disequilibrium test, were likewise non-significant. The results reported here provide little support for the role of these polymorphisms in panic disorder.

Topics: Cholecystokinin; Family Health; Fluorescence Polarization; Genetic Linkage; Humans; Microsatellite Repeats; Panic Disorder; Polymorphism, Genetic; Receptor, Cholecystokinin B; Receptors, Cholecystokinin

A growing body of evidence suggests that idiopathic environmental intolerance (IEI) is a psychophysiologic disorder with prominent features of anxiety/panic and somatization, although proponents of a toxicogenic explanation claim, despite a lack of convincing evidence, that symptoms arise from exposure to otherwise nonnoxious environmental agents. Patient behaviour is characterized by strenuous avoidance of perceived triggers to the point of severe impairment of normal social and vocational functioning. IEI proponents claim that previous studies showing a high prevalence of psychopathology in patients with IEI and studies showing panic responses to known panicogenic challenges merely reflect the anxiety-producing result of living with IEI.. We explored whether IEI and panic disorder, personality traits, or both shared an underlying neurogenetic basis that would predate the anxiety of IEI symptomatology. The DNA of patients with IEI was examined for the presence of known panic disorder-associated cholecystokinin B (CCK-B) receptor alleles and for personality trait-associated dopamine D4 receptor polymorphisms.. Eleven patients with typical IEI symptoms were recruited and were individually matched to normal control subjects from an existing bank for age, sex, and ethnic background. Genomic DNA was extracted from peripheral blood samples. CCK-B and dopamine D4 receptor polymorphisms were examined by using standard PCR-based techniques.. There was a significantly higher prevalence of the panic disorder-associated CCK-B receptor allele 7 in subjects with IEI (9/22 [40.9%]) compared with control subjects (2/22 [9.1%], P =.037). There was no difference in personality trait-associated polymorphisms of the gene encoding dopamine D4 receptor between patients and control subjects.. These findings provide preliminary evidence that IEI and panic disorder share a common neurogenetic basis, which would predate the anxiety-producing effects of IEI symptoms. Further studies with larger samples are warranted, but these results support previous studies that suggest that panic disorder may account for much of the symptomatology in at least some cases of IEI and provide a basis for rational treatment strategies.

Topics: Alleles; Avoidance Learning; Cholecystokinin; Dopamine; Exons; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Multiple Chemical Sensitivity; Panic Disorder; Polymorphism, Genetic; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Receptors, Dopamine D2; Receptors, Dopamine D4

The cholecystokinin gene (CCK) is thought to play a role in the pathogenesis of both panic disorder and schizophrenia. In this study, we have extended the 5'-upstream sequence of the CCK gene, and identified a compound short tandem repeat (STR), located approximately -2.2 to -1.8 kb from the cap site. This STR was found to be polymorphic with ten different allele lengths. Case-control studies using 73 panic patients, 305 schizophrenics and 252 controls showed a significant allelic association with panic disorder (P = 0.025), but not with schizophrenia. Dividing the STR alleles into three classes according to length, Long (L), Medium (M) and Short (S), produced strong genotypic (MM) (nominal P = 0.0014) and allelic (M) (nominal P = 0.0079) associations with panic disorder. screening the newly extended promoter region detected not only the previously identified -36c>t and -188a>g single nucleotide polymorphisms (SNPs) but a new rare snp, -345g>C. Neither of the former two SNPs showed significant association with either panic disorder or schizophrenia. Haplotypic distributions of the STR and SNPs -188 and -36 were significantly different between panic samples and controls (P = 0.0003). These findings suggest that the novel STR or a nearby variant may confer susceptibility to the development of panic disorder.

Topics: 5' Untranslated Regions; Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Base Sequence; Cholecystokinin; DNA; Female; Genotype; Humans; Linkage Disequilibrium; Male; Middle Aged; Molecular Sequence Data; Monte Carlo Method; Panic Disorder; Polymorphism, Genetic; Reference Values; Repetitive Sequences, Nucleic Acid; Schizophrenia

There is evidence for the role of the cholecystokinin (CCK) neurotransmitter system in the neurobiology of panic disorder (PD). The CCK receptor agonist, CCK-tetrapeptide (CCK-4) fulfills criteria for a panicogenic agent and there is evidence that PD might be associated with an abnormal function of the CCK system. For example, PD patients show an enhanced sensitivity to CCK-4, and exhibit lower CSF and lymphocyte CCK concentration as compared to healthy controls (reviewed by Bradwejn et al.). Also, untreated PD patients display an increased CCK-4-induced intracellular Ca2+ mobilization in T cells relative to treated PD, depression and schizophrenia. The CCK receptors have been classified into two subtypes: CCK-A and CCK-B. We report here a study of polymorphisms in the CCK pre-pro hormone gene (CCK), CCK-AR, and CCK-BR in DSM-IV panic patients (n = 99) vs controls matched for gender and ethnicity. The CCK polymorphism revealed no association with PD. We identified a new polymorphism for the CCK-A receptor gene, and tested it in our sample, with negative results. A single nucleotide polymorphism has been found in the coding region of the CCK-B receptor gene (CCK-BR) and D Collier (personal communication) identified a highly polymorphic dinucleotide (CT)n microsatellite in the 5' regulatory region. For the CCK-B receptor gene polymorphism, PD patients showed a significant association. Our genetic dissection of the CCK system thus far suggests that the CCK-B receptor gene variation may contribute to the neurobiology of panic disorder.

Topics: Alleles; Cholecystokinin; Female; Genotype; Humans; Male; Panic Disorder; Polymorphism, Genetic; Promoter Regions, Genetic; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Reference Values; Repetitive Sequences, Nucleic Acid

Cholecystokinin (CCK) is an abundant neurotransmitter in brain. Its functional significance in humans is incompletely understood, but it may modulate activity in the hypothalamic-pituitary-adrenal (HPA) axis. To explore this hypothesis, we examined the effects of varying doses (0 to 0.8 microgram/kg) of the CCK-B agonist pentagastrin on adrenocorticotropin (ACTH) and cortisol release in healthy human subjects. We also examined anxiety, heart rate (HR), and blood pressure (BP) responses. Pentagastrin induced large (up to 520% increase over baseline), significant and very rapid, dose-dependent elevations in ACTH and cortisol levels. Significant elevations in HR and BP were seen at all doses, without clear dose-response relationships. Anxious distress and symptom responses were also somewhat dose dependent; but hormonal responses were more robustly linked to pentagastrin dose than to these subjective measures. The HPA axis response to the CCK-B agonist pentagastrin may be a direct pharmacological effect. Further work is needed to determine the mechanisms and the physiological significance of CCK-mediated modulation of the human neuroendocrine stress axis.

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Analysis of Variance; Anxiety; Cardiovascular Physiological Phenomena; Cholecystokinin; Dose-Response Relationship, Drug; Female; Humans; Hydrocortisone; Male; Middle Aged; Panic Disorder; Pentagastrin; Pituitary-Adrenal System; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Regression Analysis

We searched for mutations in the CCK gene in panic disorder with single-strand conformational polymorphism (SSCP) analysis of the three exons and promotor region of the gene. We found a C-->T transition at position -36 (CCK(-36C-->T)) in a GC box, a binding site for transcription factor Sp1, in the promotor region. The allele frequency was 0.168 (95% CI, 0.116-0.221) in 98 persons with panic disorder and 0.083 (95% CI, 0.059-0.107) in 247 geographically matched, unscreened controls. A transmission disequilibrium test based on panic disorder as the affected phenotype was nonsignificant (chi2 = 0.93), but when panic disorder or attacks were considered as affected, statistically significant transmission disequilibrium was detected (chi2 = 4.00, P < 0.05). Linkage analysis was uninformative. In exploratory analyses to search for clinical correlations, the "T" allele was found in 59% of 22 persons with panic attacks but not panic disorder, compared with 31% of those who met the criteria for panic disorder. An association between the CCK polymorphism and panic disorder cannot be considered established due to the inconsistencies in the results noted above, but if the provisional association can be replicated, the findings are consistent with CCK(-36C-->T) being a disease-susceptibility allele that alone is neither necessary nor sufficient to cause panic disorder but that increases vulnerability by acting epistatically.

Topics: Adult; Cholecystokinin; DNA Mutational Analysis; Exons; Female; Gene Frequency; Genetic Linkage; Humans; Iceland; Iowa; Male; Middle Aged; Panic Disorder; Pedigree; Point Mutation; Polymorphism, Single-Stranded Conformational; Promoter Regions, Genetic

Levels of the enzyme N-acetyl-beta-glucosaminidase (NAG) and a mutation of cholecystokinin (CCK) gene appear to be independently associated with panic disorder. We explored whether there was an association of NAG levels and a CCK mutation identified in a group of panic disorder patients. NAG was measured in 12 panic disorder patients who had a mutation of the CCK gene and 17 who did not. Urine for NAG was collected at baseline and after 3 and 6 weeks of treatment. NAG levels were lower at all three times in the patients that did not have the CCK mutation. The difference between the two groups was significant at week 6 (P < 0.02), and showed a trend toward a difference at baseline (P < 0.15).

Topics: Acetylglucosaminidase; Adult; Cholecystokinin; Humans; Mutation; Panic Disorder

Topics: Animals; Cholecystokinin; Humans; Neuropharmacology; Panic Disorder; Receptors, Cholecystokinin

Topics: Animals; Anxiety Disorders; Cholecystokinin; Humans; Panic Disorder

Cholecystokinin concentrations in the CSF of 25 patients with panic disorder and 16 normal comparison subjects were ascertained by radioimmunoassay. The patients with panic disorder had significantly lower CSF concentrations of cholecystokinin, which may reflect increased CNS cholecystokinin receptor sensitivity, reduced numbers of receptors, or a compensatory reduction in cholecystokinin octapeptide secondary to theoretically increased central cholecystokinin tetrapeptide activity.

Topics: Adolescent; Adult; Brain; Cholecystokinin; Female; Humans; Middle Aged; Panic Disorder; Receptors, Cholecystokinin; Sincalide; Tetragastrin