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Biomedical subjects

J Bradwejn

Publications and source records attributed to J Bradwejn.

At least 19 recordsLinked to original sources
PubMed2002

The ventilatory response to cholecystokinin tetrapeptide in healthy volunteers.

The cholecystokinin (CCK) system, which has been shown to interact with both the panicogenic and respiratory systems, provides an interesting mechanism to further evaluate the central chemoreceptor and its effect on panic attack sensitivity. Intravenous CCK, a naturally occurring neuropeptide in the brain, has been found to induce the emotional and somatic symptoms of panic in both Panic Disorder (PD) and Normal Control (NC) subjects in a dose-dependent and reproducible fashion. To induce these effects, lower doses of intravenous CCK are required in the PD patients, relative to the NC subjects potentially suggesting that endogenous alterations in the CCK system may be contributing to the development of PD. Intravenous administration of CCK-4 in association with panic also results in subjective dyspnea, that is, diminution in vital capacity without an effect on the respiratory resistance. CCK-4 also causes a significant increase in tidal volume and minute ventilation but has no effect on breathing frequency. These observations suggest that a CCK-B receptor agonist may be acting as a respiratory stimulant, exerting its effect on anxiety through a direct effect on respiration. This study represents an examination of the specific effects of CCK-4 on the central chemoreceptor response. The study used a modified rebreathing technique, which accurately measures the ventilatory response to carbon dioxide in terms of both threshold and sensitivity. This technique requires the subject to rebreathe from a bag containing a hyperoxic and hypercapnic gas mixture resulting in rapid equilibration between alveolar gas and arterial blood. Use of a hyperoxic gas allows for the preferential examination of the central chemoreflexes (sensitive to CO(2)) with little if any effect of the peripheral (oxygen sensitive) chemoreflexes. After significant training, 15 healthy control subjects were assigned via a double blind procedure to receive an intravenous injection of placebo or CCK-4, using a between-subjects design. A between-subjects comparison was undertaken for the injection run (run #3) between subjects receiving the CCK-4 injection and those receiving the placebo injection. As well, a within-subject comparison was undertaken to compare the results of the run following the injection (run #3) vs. the previous run when no injection took place (run #2). No significant differences were noted between subjects who received CCK-4 as compared with placebo for: basal or sub-threshold ventilation, threshold CO(2) resulting in a change in ventilation, or sensitivity of the central chemoreflex, regardless of whether a panic attack did or did not take place. In addition, within the group receiving the CCK-4 challenge, no significant differences were noted during run #3 (received the CCK-4 injection) and a prior run where no injection took place (run #2). We conclude that CCK-4 does not act to induce panic by altering the central (CO(2) sensitive) chemoreceptor.

Analysis of Variance↗
PubMed2001

Anxiety sensitivity does not predict fearful responding to 35% carbon dioxide in patients with panic disorder.

The aim of the present study was to examine the relationship between anxiety sensitivity, as measured by the Anxiety Sensitivity Index (ASI), and four dimensions of behavioural reactivity to a single inhalation of 35% carbon dioxide (CO(2)) in 31 patients with panic disorder. ASI scores correlated positively with baseline State-Trait Anxiety Inventory scores but did not correlate with post-CO(2) scores. Correlational analyses revealed a significant, albeit modest, correlation between anxiety sensitivity and cognitive symptoms induced with CO(2). However, no significant association was found between anxiety sensitivity and other dimensions of CO(2)-induced anxiety, including severity of somatic symptoms, subjective levels of anxiety, fear or apprehension, and fear of the somatic symptoms induced by CO(2). Overall, these data do not support the view that anxiety sensitivity plays a key role in mediating behavioural sensitivity to CO(2) inhalation in panic disorder.

Administration, Inhalation↗
PubMed2001

The influence of Type A behavior pattern on the response to the panicogenic agent CCK-4.

OBJECTIVES: Review of the literature equivocally suggests that subjects with Type A behavioral pattern (TABP) compared to subjects with Type B behavioral pattern display an increased sympathetic activity, a condition associated with sudden cardiac death. The objective of this study was to determine whether healthy subjects classified as Type A or Type B differed in their reactivity to the beta 1 and beta 2 receptor agonist isoproterenol and to the panicogenic agent cholecystokinin-tetrapeptide (CCK-4). By comparing reactivity to CCK-4 after pretreatment with placebo or propranolol, a beta 1 and beta 2 receptor antagonist, the role of the beta adrenergic system in the hypothesized increased response of Type A subjects to CCK-4 was also assessed. METHODS: The study used a randomized, double-blind, placebo-controlled design. Twenty-seven Type A or B subjects were included in the study. The reactivity to isoproterenol was assessed with the CD25 of isoproterenol (i.e., the intravenous dose of isoproterenol necessary to increase the heart rate of 25 bpm). The panic symptom response and the cardiovascular response to bolus injection of 50 microg of CCK-4 was assessed in subjects pretreated with either propranolol or placebo infusions prior to the CCK-4 challenge. An additional group of subjects was recruited and these subjects received a placebo infusion pretreatment before an injection of placebo. RESULTS: The CD25 was significantly greater in Type A subjects than in Type B subjects. No difference was found among the groups on behavioral sensitivity to the CCK-4 challenge. However, CCK-4-induced maximum increase in heart rate was greater in Type A subjects. CONCLUSION: Our finding that Type A subjects exhibited greater CD25 of isoproterenol and greater increases in heart rate following CCK-4 administration compared to Type B subjects suggests that peripheral beta-receptor sensitivity may be increased in individuals with TABP.

Adrenergic beta-Agonists↗
PubMed2001

Arginine-vasopressin and oxytocin response to cholecystokinin-tetrapeptide.

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.

Adult↗
PubMed2001

Cholecystokinin and panic disorder: past and future clinical research strategies.

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.

Cholecystokinin↗
PubMed2000

Neurohormonal responses to cholecystokinin tetrapeptide: a comparison of younger and older healthy subjects.

We recently found that, compared with younger healthy subjects, older healthy subjects had less symptomatic and cardiovascular response to the panicogenic agent cholecystokinin tetrapeptide (CCK-4). As an exploratory part of that study, we also evaluated the effect of aging on neurohormonal responses to CCK-4. These hormonal data are the focus of this article. Forty healthy volunteers aged 20-35 years and 40 healthy volunteers aged 65-81 years, divided equally between men and women, were compared on their hormonal responses (maximum change from baseline in growth hormone [GH], prolactin, adrenocorticotropic hormone [ACTH], and cortisol) to the intravenous administration of 50 microg of CCK-4 or placebo. Blood samples for serum hormone determination were collected at 2 minutes prior to the intravenous challenge (baseline) and at 2, 5, and 10 minutes after the challenge. In both age groups, maximum increase in prolactin, ACTH and cortisol was significantly greater with CCK-4 than with placebo. Following administration of CCK-4, younger and older groups did not significantly differ in maximum increase in prolactin, ACTH, or cortisol. Older subjects had a statistically significant smaller increase in GH compared with younger subjects but the magnitude of the difference was small and of doubtful clinical relevance. Older subjects who had a panic attack had significantly greater elevations of all hormones compared with those who did not panic and younger panickers had a significantly greater elevation of GH compared with young nonpanickers. For the most part, maximum changes in hormonal levels were not correlated with symptom severity, suggesting that other factors may have contributed to the differential effect of panic on the HPA axis.

Adrenocorticotropic Hormone↗
PubMed2000

A double-blind, placebo-controlled study on the effects of Gotu Kola (Centella asiatica) on acoustic startle response in healthy subjects.

Investigations of the pharmacologic profile of medicinal plants have revealed that a number of plants with purported anxiolytic activity bind to cholecystokinin (CCK) receptors. This finding is intriguing in view of the proposed involvement of CCK in the pathophysiology of fear and anxiety. This double-blind, placebo-controlled study was undertaken to evaluate the anxiolytic activity of Gotu Kola (Centella asiatica) in healthy subjects. Gotu Kola has been used for centuries in Ayurvedic and traditional Chinese medicine to alleviate symptoms of depression and anxiety. Recent studies in the rat have shown that long-term pretreatment with Gotu Kola decreases locomotor activity, enhances elevated-plus maze performance, and attenuates the acoustic startle response (ASR). In this study, the authors evaluated the effects of Gotu Kola on the ASR in humans. Subjects were randomly assigned to receive either a single 12-g orally administered dose of Gotu Kola (N = 20) or placebo (N = 20). The results revealed that compared with placebo, Gotu Kola significantly attenuated the peak ASR amplitude 30 and 60 minutes after treatment. Gotu Kola had no significant effect on self-rated mood, heart rate, or blood pressure. These preliminary findings suggest that Gotu Kola has anxiolytic activity in humans as revealed by the ASR. It remains to be seen whether this herb has therapeutic efficacy in the treatment of anxiety syndromes.

Acoustic Stimulation↗
PubMed1999

Neuroanatomic correlates of CCK-4-induced panic attacks in healthy humans: a comparison of two time points.

BACKGROUND: Several functional imaging studies have demonstrated increases of brain activity in the temporofrontal, cingulate, and claustrum regions during a pharmacologically induced panic attack when scanning was done at a single point in time. However, no study has evaluated changes in brain activity at two time points during a panic attack. We hypothesized that in response to a single bolus injection of the panicogen cholecystokinin-4 (CCK-4) in healthy volunteers, changes in regional cerebral blood flow (rCBF) might be different if scanning were done at two different time points. METHODS: To test this hypothesis, we conducted a single-blind study, using positron emission tomography (PET). To determine the time effect of panic attack on brain activity, we performed either early scan or late scan covering the first or the second minute after CCK-4 bolus injection, respectively. The PET images were analyzed by statistical parametric mapping (SPM) followed by region of interest (ROI) analysis. RESULTS: The results showed significant differences between the early and the late scan. The early effects of CCK-4 are accompanied by increases in rCBF in the hypothalamic region, whereas the late scan showed an increase in rCBF in the claustrum-insular region. Reductions in rCBF were observed for both time groups in the medial frontal region. A separate scan for anticipatory anxiety demonstrated rCBF increases in the anterior cingulate region and decreases in the occipital regions. CONCLUSIONS: These results may support the hypothesis that changes in rCBF as a function of time during CCK-4-induced panic might correspond to a neurocircuitry involved in panic attacks.

Adult↗
PubMed1999

Sensitivity to CCK-4 in women with and without premenstrual dysphoric disorder (PMDD) during their follicular and luteal phases.

The authors determined whether women with premenstrual dysphoric disorder (PMDD) exhibit a heightened sensitivity to the panicogenic effects of CCK-4 administration and whether this enhanced sensitivity to CCK-4 would vary with the phase of the menstrual cycle at the time of CCK-4 injection. Twenty-one normal controls and 18 PMDD women were randomly assigned to receive the first and second CCK-4 injection during the follicular phase and the luteal phase or vice versa. PMDD women showed a greater anxiety and panic response to CCK-4. These preliminary results suggest that the CCK-B system may play a role in the pathophysiology of PMDD.

Adult↗
PubMed1999

Acute and chronic role of 5-HT3 neuronal system on behavioral and neuroendocrine changes induced by intravenous cholecystokinin tetrapeptide administration in humans.

The influence of single and multiple oral doses of ondansetron, a selective 5-HT3 receptor antagonist, was evaluated against placebo on cholecystokinin tetrapeptide (CCK-4)-induced behavioral and neuroendocrine changes in humans. As compared to placebo, subjects receiving acute ondansetron treatment showed a significant decrease in the sum intensity of CCK-4-induced-panic symptoms (iPSS). Pre-CCK-4 neuropeptide Y (NPY) plasma levels were significantly higher and maximal changes in cortisol, growth hormone, and prolactin secretion from baseline (delta max) were significantly lower in the ondansetron group. After ondansetron and placebo chronic administration, there were no statistical differences in the iPSS between groups. Pre-CCK-4 NPY plasma levels were significantly higher; whereas, delta max for NPY significantly lower in the ondansetron group as compared to placebo. These results suggest a role for the 5-HT3 receptor in the neurobiology of panic disorder through a possible interaction with CCK and NPY systems. Ondansetron chronic effect on CCK-4-induced behavioral changes needs further exploration.

Adolescent↗
PubMed1999

CCK4-induced panic in healthy subjects I: psychological and cardiovascular effects.

Sixteen healthy subjects participated in a crossover, double blind, and placebo-controlled study, designed to assess simultaneously the psychological and cardiovascular effects of cholecystokinin tetrapeptide (CCK4). Following an i.v. injection of 25 microg of CCK4, 44 percent of subjects experienced symptoms that fulfilled the DSM-IV criteria for a panic attack while no one panicked with placebo. CCK4 induced a significantly greater number and higher intensity of panic-like symptoms than placebo. A significant increase in state anxiety was observed in the period after CCK4 injection; this increase was significantly larger than the non-specific anxious reaction to placebo. CCK4 also affected cardiovascular signs. Both heart rate and mean blood pressure significantly increased after administration of CCK4. Again, these increases were significantly higher than those seen after placebo injection. We conclude that, in healthy subjects, CCK4 induces panic-like reaction characterized by a number of somatic, cognitive and emotional symptoms, which are accompanied by increases in heart rate and blood pressure.

Adult↗
PubMed1999

CCK4-induced panic in healthy subjects II: neurochemical correlates.

Cholecystokinin tetrapeptide (CCK4) induces symptoms similar to those of panic attack. The present study investigated the effects of CCK4 administration on catecholaminergic system. In this double blind, randomised, crossover experiment, 16 healthy subjects received injections of either 25 microg of CCK4 or placebo on two separate occasions. Platelet and plasma catecholamine concentrations were assessed before the administration and compared to post-injection values. The results clearly show that both plasma and platelet concentrations of catecholamines are significantly affected by CCK4. Plasma norepinephrine (NE) and epinephrine (EPI) raised significantly above baseline in the immediate post-CCK4 period, while in plasma dopamine (DA), the significant increases were delayed. In the platelets, significant post-CCK4 increases of NE and EPI concentrations were observed with a delay of several minutes. In summary, we have demonstrated that, in healthy subjects, CCK4 increases peripheral concentrations of catecholamines in both plasma and platelets, with the most consistent changes occurring in platelet NE and plasma EPI concentrations.

Adult↗
PubMed1999

Investigation of cholecystokinin system genes in panic disorder.

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.

Alleles↗
PubMed1999

Effects of CCK-4 infusion on the acoustic eye-blink startle and psychophysiological measures in healthy volunteers.

The acoustic startle response (ASR) and a range of psychophysiological parameters were evaluated during a continuous intravenous administration of cholecystokinin-tetrapeptide (CCK-4) in healthy volunteers. Subjects (n=28) were randomly assigned to double-blind infusion of either CCK-4 (0.5 mg/60 min) or placebo. The ASR sessions were performed prior to infusion and at 20 min and 50 min after the onset of infusion by recording eye-blink response to a series of acoustic stimuli (110 dB, 40 ms). An effect of CCK-4 on the eye-blink startle was observed in the first half of infusion. CCK-4 produced an increase of eye-blink startle amplitude from baseline values in contrast to the decrease observed at this time point with placebo. A mild increase in anxiety and heart rate followed by fatigue was reported with CCK-4. Administration of CCK-4 produced increases in plasma concentrations of adrenocorticotropic hormone, cortisol, prolactin and growth hormone. The results of this study show that a prolonged intravenous administration of CCK-4 may be a useful challenge method for further studies on the role of CCK system in the modulation of human anxiety and stress response.

Acoustic Stimulation↗
PubMed1998

The role of the beta-noradrenergic system in cholecystokinin-tetrapeptide-induced panic symptoms.

BACKGROUND: The authors determined whether effective beta-adrenergic blockade could attenuate the panicogenic effects of cholecystokinin-tetrapeptide (CCK-4) in healthy volunteers. METHODS: Subjects were randomly assigned to either a propranolol (n = 14) or placebo (n = 16) infusion. Ten minutes after completion of the infusion subjects received a bolus injection of CCK-4 (50 micrograms). RESULTS: Acute pretreatment with propranolol was more effective than placebo in decreasing behavioral and cardiovascular sensitivity. CONCLUSIONS: These preliminary results suggest that the panicogenic effects of CCK-4 are mediated, in part, through the beta-adrenergic system.

Adult↗
PubMed1998

Neurobiology of panic disorder.

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.

Caffeine↗