CCK-4 Research Articles

Influence of Retrodipeptide Analogue of Cholecystokinin Tetrapeptide (GB-115) and Phenazepam on the Behavior of Rhesus Monkeys under Isolation Conditions.

The developed domestic retrodipeptide analogue of cholecystokinin tetrapeptide (CCK) (N-(6-phenylhexanoyl)-glycyltryptophan amide, or compound GB-115) with antagonistic properties in relation to CCK1 receptors has anxiolytic activity previously shown in preclinical and clinical studies. The aim of the study was to evaluate the anxiolytic effect of GB-115 as a tablet form with subchronic oral administration in comparison with phenazepam in nonhuman primates. The study was conducted on four male rhesus monkeys (Macaca mulatta) aged 5.7-6.7 years. After a 30-day adaptation to the conditions of individual caging, experiments were performed first with GB-115 (tablets of 0.001 g) and second with phenazepam (tablets of 0.0005 g). Both drugs were administered one at a time (7 days) and then two tablets each (7 days). Behavior was assessed by observing an object with registration according to the "Yes-No" principle of ethogram elements at the background periods, during the administration of the drugs, and after their withdrawal. The stress response was assessed using cortisol and dehydroepiandrosterone sulfate (DHEA-S) levels as biomarkers determined in the blood serum by enzyme immunoassay. GB-115 (0.001 g each) and phenazepam (0.001 g each) decreased the stay of the animals in the upper part of the cage compared to the background period, indicating decrease in stress response. GB-115 (0.002 g each) reduced the cortisol/DHEA-S ratio. Phenazepam dose-dependently decreased the level of cortisol in the blood serum without affecting the content of DHEA-S. Under administration of phenazepam (0.001 g each), a decreased cortisol/DHEA-S ratio was also observed. A positive effect of GB-115 upon subchronic administration on the attenuation of the emotional stress response and the restoration of adaptive behavior in rhesus monkeys comparable to the effect of phenazepam was revealed, which confirms the possibility of using blockade of CCK1 receptors as one of the approaches for treating anxiety disorders.

Effect of the dipeptide retro-analog of cholecystokinin tetrapeptide (GB-115) on the behavior of rhesus monkeys in isolation

Introduction. The developed domestic dipeptide retro-analog of cholecystokinin (CCK) tetrapeptide (N-(6-phenylhexanoyl)-glycyltryptophan amide, compound GB-115) with antagonistic properties towards CCK1 receptors has anxiolytic activity, previously shown in preclinical and clinical studies. Purpose of the study. Evaluation of the anxiolytic effect of GB-115 in tablet dosage form with subchronic oral administration in comparison with phenazepam in laboratory primates. Methods. The experiment was performed on four male rhesus monkeys (Macaca mulatta) aged 5.7–6.7 years. After a 30-day period of adaptation to the conditions of individual housing, an experiment was performed with GB-115 (0.001 g tablets) and then with phenazepam (0.0005 g tablets). Both drugs were given one at a time (7 days), and then 2 tablets (7 days). Behavior was assessed by observing the object with registration according to the “Yes-No” principle of ethogram elements in the background periods, during the administration of drugs and during their withdrawal. Using enzyme immunoassay, the content of stress response biomarkers: cortisol and dehydroepiandrosterone sulfate (DHEA-S) was determined in blood serum. Results. GB-115 (0.001 g each) and phenazepam (0.001 g each) reduced the stay of animals in the upper part of the cage compared to the background period, which indicates a decrease in the stress response. GB-115 (0.002 g each) decreased the cortisol/DHEA-S ratio. Phenazepam dose-dependently reduced serum cortisol levels without affecting DHEA-S levels; with the administration of phenazepam (0.001 g), a decrease in the cortisol/DHEA-S ratio was also recorded. Conclusion. A positive effect of GB-115, when administered subchronically, on the weakening of the emotional stress reaction and restoration of adaptive behavior in rhesus monkeys was revealed, comparable to the effect of phenazepam, which confirms the possibility of using blockade of CCK1 receptors as one of the approaches for the treatment of anxiety disorders.

Identification of cholecystokinin tetrapeptide amide metabolites in liver microsomes of human, Rhesus Monkey, Sprague-Dawley rat and CD1 mouse using ultra-high performance liquid chromatography coupled to high resolution mass spectrometer

Endogenous cholecystokinin tetrapeptide (CCK-4, Trp-Met-Asp-Phe-NH2) is a fragment derived from a larger peptide hormone, cholecystokinin (or gastrin). As a panicogenic agent, CCK-4 is commonly used in clinic settings to induce panic attacks for the study of new anxiolytic drugs. However, few studies on CCK-4 metabolism have been published to date. In the present study, we investigate the metabolism of CCK-4 in liver microsomes of human (HLM), Rhesus Monkey (RMLM), Sprague-Dawley rat (RLM) and CD1 mouse (MLM) using ultra-high performance liquid chromatography coupled to a high resolution mass spetrometer. Ten metabolites, inlcuding tryptophan (M1), tryptophan amide (M2), hydroxy metabolites (M3-M5), truncated peptides (M6-M9), and CCK-4 acid (M10), were identified and 8 of them were reported for the first time. The metabolic pattern of CCK-4 in HLM was distinctly different from these in RMLM, RLM, and MLM. M2 and M9 were the major metabolites in HLM and accounted for 19.8% and 13.4% of initial CCK-4, respectively. In contrast, M2 was the major metabolite in RMLM and accounted for 41.4%, whereas M6 was the major metabolite in RLM and account for 39.1%. Three major metabolites M2, M7 and M8 in MLM accounted for 22.6%, 17.9% and 17.8% of initial CCK-4, respectively. Chemical inhibition experiment showed that aminopeptidase and/or endopeptidase hydrolysis were the major metabolic pathways in human to generate these metabolites. We further showed that cytochrome P450 were also involved in the metabolism of CCK-4 via hydroxylation, but to a less extend. These findings provide valuable information for the metabolic processes of CCK-4 among various species and an important reference basis for its safety evaluation and rational clinical application.

Treatment with HC-070, a potent inhibitor of TRPC4 and TRPC5, leads to anxiolytic and antidepressant effects in mice.

BackgroundForty million adults in the US suffer from anxiety disorders, making these the most common forms of mental illness. Transient receptor potential channel canonical subfamily (TRPC) members 4 and 5 are non-selective cation channels highly expressed in regions of the cortex and amygdala, areas thought to be important in regulating anxiety. Previous work with null mice suggests that inhibition of TRPC4 and TRPC5 may have anxiolytic effects.HC-070 in vitroTo assess the potential of TRPC4/5 inhibitors as an avenue for treatment, we invented a highly potent, small molecule antagonist of TRPC4 and TRPC5 which we call HC-070. HC-070 inhibits recombinant TRPC4 and TRPC5 homomultimers in heterologous expression systems with nanomolar potency. It also inhibits TRPC1/5 and TRPC1/4 heteromultimers with similar potency and reduces responses evoked by cholecystokinin tetrapeptide (CCK-4) in the amygdala. The compound is >400-fold selective over a wide range of molecular targets including ion channels, receptors, and kinases.HC-070 in vivoUpon oral dosing in mice, HC-070 achieves exposure levels in the brain and plasma deemed sufficient to test behavioral activity. Treatment with HC-070 attenuates the anxiogenic effect of CCK-4 in the elevated plus maze (EPM). The compound recapitulates the phenotype observed in both null TRPC4 and TRPC5 mice in a standard EPM. Anxiolytic and anti-depressant effects of HC-070 are also observed in pharmacological in vivo tests including marble burying, tail suspension and forced swim. Furthermore, HC-070 ameliorates the increased fear memory induced by chronic social stress. A careful evaluation of the pharmacokinetic-pharmacodynamic relationship reveals that substantial efficacy is observed at unbound brain levels similar to, or even lower than, the 50% inhibitory concentration (IC50) recorded in vitro, increasing confidence that the observed effects are indeed mediated by TRPC4 and/or TRPC5 inhibition. Together, this experimental data set introduces a novel, high quality, small molecule antagonist of TRPC4 and TRPC5 containing channels and supports the targeting of TRPC4 and TRPC5 channels as a new mechanism of action for the treatment of psychiatric symptoms.

Reversible Morphological Control of Cholecystokinin Tetrapeptide Amyloid Assemblies as a Function of pH.

Most amyloid assemblies are seen as irreversible and exhibit polymorphism because their assembly is kinetically controlled and different structures are trapped during the aggregation process. However, in the specific case of peptide hormones, formation of amyloid assemblies for storage purposes has been reported. This suggests a strict control of assembly and the ability to disassemble upon hormone secretion. In the present work, we have sought to test these assertions with a short peptide, the cholecystokinin (or gastrin) tetrapeptide (CCK-4), that has been found in both gastrointestinal tract and central nervous system, and whose sequence is shared by a large number of hormones. We have thus studied in vitro this peptide's self-assembling properties in dense phases at different pH levels, thus mimicking in vivo storage conditions. The solubility and morphology of the supramolecular assemblies have been shown to vary with the pH. At low pH, the tetrapeptide exhibits a low solubility and forms microcrystals. At higher pH levels, peptide solubility increases and above a high enough concentration, peptide monomers self-assemble into typical amyloid fibrils of 10-20 nm diameter. The physical network formed by these fibrils results in a birefringent hydrogel phase. Despite the different morphological features exhibited at different pH, structural analysis shows strong similarities. Both supramolecular assemblies-microcrystals and fibrils-are structured by β-sheets. We also show that all these morphologies are reversible and can be either dissolved or changed into one another by switching the pH. In addition, we demonstrate that a modification in the charge sequence of the peptide by amino acid mutation modifies its self-assembly properties. In conclusion, just as the CCK-4 sequence is the minimal sequence required for a complete biological activity at CCKB receptors in the brain, it is also sufficient to form amyloid fibers whose properties can be related to hormone storage and release purposes in vivo.

Metabotropic glutamate2/3 receptor agonism facilitates autonomic recovery after pharmacological panic challenge in healthy humans.

Group II metabotropic glutamate receptors (mGluR2/3) are suggested to modulate anxiety, arousal, and stress including autonomic control. However, no study has investigated mGluR2/3-related effects on baseline autonomic activity and reactivity to emotional challenge in humans as yet. Using a double-blind, randomized placebo-controlled, cross-over study design, we investigated the influence of a 1-week treatment with the mGluR2/3 agonist LY544344, prodrug of LY354740, on autonomic reactivity to a cholecystokinin tetrapeptide (CCK-4) panic challenge in eight healthy young men. The main outcome measures were time and frequency domain heart rate variability parameters during baseline, CCK-4 challenge, and recovery. There was no evidence for LY544344-mediated effects on baseline and CCK-4 challenge vagal activity, but a significantly lower recovery low frequency (%) and low frequency/high frequency ratio in the LY544344 group, suggesting enhanced autonomic recovery. This pilot study provides first human data indicating that mGluR2/3 agonism is involved in autonomic responsiveness, suggesting an important role of mGluR2/3 in central autonomic regulation.

Neuropeptide S receptor gene variation modulates glutamatergic anterior cingulate cortex activity during CCK-4 induced panic

An excitatory-inhibitory neurotransmitter dysbalance has been suggested in pathogenesis of panic disorder. The neuropeptide S(NPS)system has been implicated in modulating GABA and glutamate neurotransmission in animal models and to genetically drive altered fear circuit function and an increased risk of panic disorder in humans. Probing a multi-level imaging genetic risk model of panic, in the present magnetic resonance spectroscopy (MRS) study brain glutamate+glutamine (Glx) levels in the bilateral anterior cingulate cortex (ACC) during a pharmacological cholecystokinin tetrapeptide (CCK-4) panic challenge were assessed depending on the functional neuropeptide S receptor gene (NPSR1) rs324981 A/T variant in a final sample of 35 healthy male subjects. The subjective panic response (Panic Symptom Scale; PSS) as well as cortisol and ACTH levels were ascertained throughout the experiment. CCK-4 injection was followed by a strong panic response. A significant time x genotype interaction was detected (p = .008), with significantly lower anterior cingulate Glx/Cr levels in T allele carriers as compared to AA homozygotes 5 minutes after injection (p = .003). CCK-4 induced significant HPA axis stimulation, but no effect of genotype was discerned. The present pilot data suggests NPSR1 gene variation to modulate glutamatergic activity in the ACC during acute states of stress and anxiety, with blunted, i. e. possibly maladaptive ACC glutamatergic reactivity in T risk allele carriers.

Neuropeptide S receptor gene variation modulates anterior cingulate cortex Glx levels during CCK-4 induced panic

An excitatory-inhibitory neurotransmitter dysbalance has been suggested in pathogenesis of panic disorder. The neuropeptide S (NPS) system has been implicated in modulating GABA and glutamate neurotransmission in animal models and to genetically drive altered fear circuit function and an increased risk of panic disorder in humans.Probing a multi-level imaging genetic risk model of panic, in the present magnetic resonance spectroscopy (MRS) study brain glutamate+glutamine (Glx) levels in the bilateral anterior cingulate cortex (ACC) during a pharmacological cholecystokinin tetrapeptide (CCK-4) panic challenge were assessed depending on the functional neuropeptide S receptor gene (NPSR1) rs324981 A/T variant in a final sample of 35 healthy male subjects. The subjective panic response (Panic Symptom Scale; PSS) as well as cortisol and ACTH levels were ascertained throughout the experiment.CCK-4 injection was followed by a strong panic response. A significant time×genotype interaction was detected (p=.008), with significantly lower ACC Glx/Cr levels in T allele carriers as compared to AA homozygotes 5min after injection (p=.003). CCK-4 induced significant HPA axis stimulation, but no effect of genotype was discerned.The present pilot data suggests NPSR1 gene variation to modulate Glx levels in the ACC during acute states of stress and anxiety, with blunted, i.e. possibly maladaptive ACC glutamatergic reactivity in T risk allele carriers. Our results underline the notion of a genetically driven rapid and dynamic response mechanism in the neural regulation of human anxiety and further strengthen the emerging role of the NPS system in anxiety.

Blunted autonomic reactivity to pharmacological panic challenge under long-term escitalopram treatment in healthy men.

Background:Central serotonergic pathways influence brain areas involved in vagal cardiovascular regulation and, thereby, influence sympathetic efferent activity. Selective serotonin reuptake inhibitors (SSRIs) affect multiple serotonergic pathways, including central autonomic pathways. However, only a few studies have assessed SSRI-mediated effects on autonomic reactivity in healthy individuals using heart rate variability (HRV).Methods:The present study assessed the influence of long-term treatment with escitalopram (ESC) on autonomic reactivity to an intravenous application of 50 µg cholecystokinin tetrapeptide (CCK-4) in 30 healthy young men using a double-blind, placebo (PLA)-controlled, randomized, within-subject cross-over design. Main outcome measures were time- and frequency-domain HRV parameters, assessed at both baseline and immediately after CCK-4 application.Results:Results showed substantial effects for the treatment × CCK-4 challenge interaction with respect to heart rate (p < 0.001; pη2 = 0.499), SDNN (p < 0.001; pη2 = 576), RMSSD (p = 0.015; pη2 = 194), NN50% (p = 0.008; pη2 = 0.224), and LF% (p = 0.014; pη2 = 0.196), and moderate effects with respect HF% (p = 0.099; pη2 = 0.094), with PLA subjects showing a higher increase in HR and SDNN and a higher decrease in RMSSD, NN50, LF and HF than subjects in the ESC condition. Thus, ESC treatment significantly blunted the autonomic reactivity to CCK-4. Secondary analysis indicated no effect of the 5-HTTLPR polymorphism on CCK-4-induced autonomic response.Conclusions:Our results support findings suggesting an effect of SSRI treatment on autonomic regulation and provide evidence that ESC treatment is associated with blunted autonomic reactivity in healthy men.

New perspectives in neurosteroid action: open questions for future research.

New perspectives in neurosteroid action: open questions for future research.

Effects of benzodiazepines on anterior cingulate cortex activity during experimentally induced panic

cholecystokinin-tetrapeptide (CCK-4) induces panic symptoms in healthy human subjects, which closely resemble spontaneously occurring panic attacks in patients and provides a safe, valid and reliable experimental model for the investigation of pathophysiological, neurobiological and pharmacological aspects of panic disorder. Benzodiazepines modulate γaminobutyric acid type A (GABAA) receptors throughout the brain. However, it is not fully understood which brain regions within anxiety related brain circuits are really responsible for their anxiolytic effects and how these regions interact. We therefore investigated whether the benzodiazepine alprazolam affects activity in distinct regions within anxiety related brain circuits in humans by means of functional magnetic resonance imaging (fMRI) and experimental induction of panic symptoms with CCK-4.

EPA-1581 - Anxiety-related neuronal responses in phobic postural vertigo

Vertigo and anxiety are frequent symptoms in both psychiatric and vertigo patients, especially in those with phobic postural vertigo (PPV). The aim of this study was the investigation of anxiety-associated functional responses in PPV patients compared to healthy controls. For that purpose cholecystokinin tetrapeptide (CCK-4), a valid model to experimentally induce anxiety symptoms, was used. 15 PPV patients and 15 matched healthy controls underwent challenges with CCK-4. During the paradigm, participants did not know the exact time point of the injection in order to separate the anticipatory and CCK-4 induced anxiety. The panic symptom scale score was assessed before and after the injection. During anticipatory anxiety healthy controls showed functional responses mainly in fronto-temporal regions. Patients suffering from PPV showed pronounced BOLD responses in the (ventral) anterior cingulate cortex (ACC), dorsolateral prefrontal cortex, orbitofrontal cortex and precuneus. In healthy subjects, CCK-4 induced anxiety was accompanied by activations in the medial and inferior frontal cortex. In PPV, the CCK-4 injection led to increased activities particularly in the ACC, the cuneus, the cerebellum, the amygdala and fronto-temporal regions. Given the fact of increased neuronal responses in emotion-related brain areas in patients with anxiety disorders these findings could provide evidence for common aspects of phobic postural vertigo and anxiety disorders.

The 5-HTTLPR genotype modulates heart rate variability and its adjustment by pharmacological panic challenge in healthy men

Abnormal serotonin transporter (5-HTT) function and autonomic nervous system (ANS) dysregulation has been proposed in panic disorder. However, in contrast to hypothalamo-pituitary-adrenocortical (HPA) functioning, ANS reactivity during panic response has yet not been investigated in humans with respect to the 5-HTT genotype. The present study assessed the influence of challenging by cholecystokinin tetrapeptide (CCK-4) on heart rate variability (HRV) measures, to monitor autonomic reactivity and its relationship to 5-HTT-linked polymorphic region (5-HTTLPR) genotypes. We hypothesized substantial effects of the 5-HTTLPR genotype on autonomic reactivity. We studied 30 healthy young men, 15 of each with the long/long (l/l) or short/short (s/s) genotype for the 5-HTTLPR. All participants received an intravenous application of 50 μg CCK-4. HRV measures were assessed in both groups at baseline and immediately after CCK-4 application. Our results indicated lower parasympathetic activity in s/s carriers during baseline, time and frequency domain measures. CCK-4 application significantly enhanced the sympathetic tone in both groups, leading to diminished group differences. A significant treatment by genotype effect indicated reduced autonomic reactivity to CCK-4 challenge in the s/s compared to l/l carriers. Our findings show enhanced sympathetic and/or diminished cardiac vagal activity under basal conditions and blunted autonomic reactivity in s/s vs. l/l carriers. Our study provides novel data supporting claims that the s/s genotype represents a genetic vulnerability factor associated with inadequate hyporeactivity to stress and extends current knowledge on the impact of the central serotonergic activity on the sympathoadrenal pathway.

Anxiety-related neuronal responses in phobic postural vertigo

Vertigo and anxiety are frequent symptoms in both psychiatric and vertigo patients, especially in those with phobic postural vertigo (PPV). The aim of this study was the investigation of anxiety-associated functional responses in PPV patients compared to healthy controls. For that purpose cholecystokinin tetrapeptide (CCK-4), a valid model to experimentally induce anxiety symptoms, was used. 15 PPV patients and 15 matched healthy controls underwent challenges with CCK-4. During the paradigm, participants did not know the exact time point of the injection in order to separate the anticipatory and CCK-4 induced anxiety. The panic symptom scale score was assessed before and after the injection. During anticipatory anxiety healthy controls showed functional responses mainly in fronto-temporal regions. Patients suffering from PPV showed pronounced BOLD responses in the (ventral) anterior cingulate cortex (ACC), dorsolateral prefrontal cortex, orbitofrontal cortex and precuneus. In healthy subjects, CCK-4 induced anxiety was accompanied by activations in the insula, the medial and inferior frontal cortex. In PPV, the CCK-4 injection led to increased activities particularly in the ACC, the insula, the cuneus, the cerebellum, the amygdala and fronto-temporal regions. Given the fact of increased neuronal responses in emotion-related brain areas in patients with anxiety disorders these findings could provide evidence for common aspects of phobic postural vertigo and anxiety disorder. This study was supported by BBF.

Acute Shift in Glutamate Concentrations Following Experimentally Induced Panic with Cholecystokinin Tetrapeptide—A 3T-MRS Study in Healthy Subjects

According to preclinical studies, glutamate has been implicated in the pathogenesis of anxiety. In order to elucidate the role of glutamate in anxiety and panic in humans, brain glutamate+glutamine (Glx) levels were measured during cholecystokinin-tetrapeptide (CCK-4)-induced panic using magnetic resonance spectroscopy (MRS). Eighteen healthy subjects underwent a CCK-4 challenge. MR spectra were obtained from the anterior cingulate cortex (ACC) using a single voxel point-resolved spectroscopy method and analyzed using LCModel. A combined fitting of Glx was performed. Panic was assessed using the Acute Panic Inventory (API) and Panic Symptom Scale (PSS) scores. Moreover, hypothalamic-pituitary-adrenal axis stimulation was monitored throughout the challenge. There was a significant panic response following CCK-4 as revealed by a marked increase in both the panic scores (API: F(1,17)=149.41; p<0.0001; PSS: F(1,17)=88.03; p<0.0001) and heart rate (HR: F(1,17)=72.79; p<0.0001). MRS measures showed a significant increase of brain Glx/creatine (Glx/Cr) levels peaking at 2-10 min after challenge (F(1,17)=15.94; p=0.001). There was also a significant increase in CCK-4-related cortisol release (F(6,11)=8.68; p=0.002). Finally, significant positive correlations were found between baseline Glx/Cr and both APImax (r=0.598; p=0.009) and maximum heart rate (HR(max)) during challenge (r=0.519; p=0.027). Our results suggest that CCK-4-induced panic is accompanied by a significant glutamate increase in the bilateral ACC. The results add to the hypothesis of a disturbance of the inhibitory-excitatory equilibrium and suggest that apart from static alterations rapid and dynamic neurochemical changes might also be relevant for the neural control of panic attacks.

Distinct Panicogenic Activity of Sodium Lactate and Cholecystokinin Tetrapeptide in Patients with Panic Disorder

The validity of experimentally induced panic attacks as a model to study the pathophysiology of panic disorder has been questioned. Unspecific, unpleasant and aversive effects as well as specific patterns of psychovegetative symptoms pointing to different subtypes of panic disorder patients have been observed. These findings raise the question of challenge paradigms as a valuable tool to identify different vulnerabilities in patients with panic disorder. We compared the two most widely studied panicogenic drugs sodium lactate and cholecystokinine tetrapeptide (CCK-4) with placebo in 25 patients with panic disorder and matched healthy control subjects. Psychophysiological changes were measured using the Acute Panic Inventory (API) and visual analogue scales for anxiety and arousal. In patients with panic disorder 18 out of 25 experienced a sodium lactate- or a CCK-4 induced panic attack. Lactate or CCK-4 induced symptoms and induced panic attacks were only correlated in healthy controls, but not in patients with panic disorder. The mechanisms of lactate and CCK-4 induced panic attacks are distinct in panic disorder patients but not in healthy controls. Different neurobiological vulnerabilities may be uncovered by different challenges.

Distinct panicogenic activity of sodium lactate and cholecystokinin tetrapeptide in patients with panic disorder

Distinct panicogenic activity of sodium lactate and cholecystokinin tetrapeptide in patients with panic disorder

Experimental panic provocation in healthy man—a translational role in anti-panic drug development?

Experimental neurochemical provocation of panic attacks in susceptible human subjects has considerably expanded our knowledge of the pathophysiology and psychopharmacology of panic disorder. Some panicogens also elicit short-lived panic-like states in healthy man. This offers the opportunity to assess the anti-panic action of drugs in proof-of-concept studies. However, from current data it is still unclear whether experimental panic in healthy man is a valid translational model. Most such studies in healthy volunteers have been performed using a cholecystokinin tetrapeptide (CCK-4) challenge. While CCK-4 panic was blocked by alprazolam pretreatment, escitalopram showed negative results in healthy man. Preliminary findings on novel investigational drugs and a few problematic results will be reviewed. Small sample sizes in many panic provocation studies, lack of dose-response aspects, and still-insufficient knowledge about the biological underpinning of experimental and spontaneous panic limit the interpretation of existing findings and should inspire further research.

ChemInform Abstract: trans-3-n-Propyl-L-proline is a Highly Favorable, Conformationally Restricted Replacement for Methionine in the C-Terminal Tetrapeptide of Cholecystokinin. Stereoselective Synthesis of 3-Allyl- and 3-n- Propyl-L-proline Derivatives fr

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One milligram of lorazepam does not decrease anxiety induced by CCK-4 in healthy volunteers: Investigation of neural correlates with BOLD MRI

Benzodiazepine effects on cholecystokinin tetrapeptide (CCK-4)-induced panic attack (PA) in humans are incompletely characterized, in particular on the neurofunctional level. This work explores the effects of lorazepam on brain activity and behavioral and physiological symptoms related to CCK-4-induced PA in healthy volunteers. Twenty-one male volunteers received 1 mg of lorazepam or placebo orally, 2 hours before an injection of 0.9% saline solution followed by 50 µg of CCK-4 during functional magnetic resonance imaging (fMRI) and heart rate recording. Panic attacks were defined using the panic symptom scale (PSS). In addition, the Y1-STAI (state anxiety) and the Bond & Lader Visual Analogue Scale (VAS) were used. Eleven subjects were classified as panickers. CCK-4 induced behavioral anxiety and cardiovascular effects along with cerebral activation in anxiety-related brain regions. Overall, lorazepam did not significantly modify the anxiogenic and cardiovascular effects of CCK-4. Regarding CCK-4-induced brain activation, lorazepam did not reduce activity in the insulae and cingulate gyrus of panickers. One milligram of lorazepam was not sufficient to reverse strong panicogenic effects, but decreased brain activity in the case of mild anxiety.