RESUMEN
Spinocerebellar ataxias (SCAs) are a group of genetic diseases characterized by progressive ataxia and neurodegeneration, often in cerebellar Purkinje neurons. A SCA1 mouse model, Pcp2-ATXN1[30Q]D776, has severe ataxia in absence of progressive Purkinje neuron degeneration and death. Previous RNA-seq analyses identify cerebellar upregulation of the peptide hormone cholecystokinin (Cck) in Pcp2-ATXN1[30Q]D776 mice. Importantly, absence of Cck1 receptor (Cck1R) in Pcp2-ATXN1[30Q]D776 mice confers a progressive disease with Purkinje neuron death. Administration of a Cck1R agonist, A71623, to Pcp2-ATXN1[30Q]D776;Cck-/- and Pcp2-AXTN1[82Q] mice dampens Purkinje neuron pathology and associated deficits in motor performance. In addition, A71623 administration improves motor performance of Pcp2-ATXN2[127Q] SCA2 mice. Moreover, the Cck1R agonist A71623 corrects mTORC1 signaling and improves expression of calbindin in cerebella of AXTN1[82Q] and ATXN2[127Q] mice. These results indicate that manipulation of the Cck-Cck1R pathway is a potential therapeutic target for treatment of diseases involving Purkinje neuron degeneration.
Asunto(s)
Quimiocinas CC/agonistas , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Células de Purkinje/efectos de los fármacos , Ataxias Espinocerebelosas/tratamiento farmacológico , Tetragastrina/análogos & derivados , Animales , Ataxina-1/genética , Ataxina-1/metabolismo , Atrofia , Conducta Animal/efectos de los fármacos , Calbindinas/metabolismo , Quimiocinas CC/genética , Quimiocinas CC/metabolismo , Colecistoquinina/genética , Colecistoquinina/metabolismo , Modelos Animales de Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Degeneración Nerviosa , Neuropéptidos/genética , Neuropéptidos/metabolismo , Células de Purkinje/enzimología , Células de Purkinje/patología , Transducción de Señal , Ataxias Espinocerebelosas/enzimología , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/patología , Tetragastrina/farmacologíaRESUMEN
Intravenous cholecystokinin-tetrapeptide (CCK-4) administration reliably and dose-dependently provokes panic anxiety in man, accompanied by adrenocorticotropic hormone (ACTH) and cortisol release. Preclinical findings suggest that behavioral and endocrine effects of CCK-4 are mediated via corticotropin-releasing hormone (CRH) release. Anxiogenic stimulation of the central CCK-receptors in man was shown to increase as well vasopressin (AVP), which acts synergistically with CRH as pituitary-adrenocortical axis stimulator during stress. Copeptin (CoP), the C-terminal part of pre-pro-AVP, is released in an equimolar ratio to AVP. It is more stable in the circulation and easier to determine than AVP and it was found to closely mirror the production of AVP. So far, CoP secretion has not been characterized during panic provocation. In 30 healthy male human subjects, we repeatedly measured CoP in plasma during a panic challenge and studied its correlation to Acute Panic Inventory (API) ratings and plasma ACTH and cortisol. CoP levels correlated positively with the increase in API ratings (r=0.41, p=0.03), while ACTH or cortisol did not (r=0.08, p=0.68 and r=0.12, p=0.53, respectively). CoP levels correlated also positively with ACTH (r=0.48, p=0.009) and cortisol (r=0.48, p=0.01) concentrations throughout the CCK-4 challenge. As expected, we found a positive correlation between plasma ACTH and cortisol levels (r=0.57, p=0.001). A vasopressinergic activation during CCK-4 induced panic was demonstrated, which was correlated positively to panic symptoms and pituitary-adrenocortical release. Our findings suggest a role of CoP as a potential surrogate marker of CCK-4 panic symptoms. Further studies are needed to replicate our results and to further clarify the role of CoP as a stress-sensitive hormone in different panic paradigms as well as in panic patients.
Asunto(s)
Hormona Adrenocorticotrópica/sangre , Ansiedad/inducido químicamente , Glicopéptidos/sangre , Hidrocortisona/sangre , Neurotransmisores/farmacología , Pánico , Receptores de Colecistoquinina/agonistas , Tetragastrina/farmacología , Adulto , Biomarcadores/sangre , Humanos , Masculino , Pánico/fisiología , Adulto JovenRESUMEN
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.
Asunto(s)
Alanina/análogos & derivados , Compuestos Bicíclicos con Puentes/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Pánico/efectos de los fármacos , Receptores de Glutamato Metabotrópico/agonistas , Tetragastrina/farmacología , Adulto , Alanina/farmacología , Estudios Cruzados , Método Doble Ciego , Voluntarios Sanos , Humanos , Masculino , Proyectos Piloto , Adulto JovenRESUMEN
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; pη(2) = 0.499), SDNN (p < 0.001; pη(2) = 576), RMSSD (p = 0.015; pη(2) = 194), NN50% (p = 0.008; pη(2) = 0.224), and LF% (p = 0.014; pη(2) = 0.196), and moderate effects with respect HF% (p = 0.099; pη(2) = 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.
Asunto(s)
Sistema Nervioso Autónomo/efectos de los fármacos , Citalopram/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Administración Intravenosa , Adulto , Sistema Nervioso Autónomo/fisiología , Citalopram/administración & dosificación , Estudios Cruzados , Método Doble Ciego , Hormonas Gastrointestinales/administración & dosificación , Hormonas Gastrointestinales/farmacología , Voluntarios Sanos , Humanos , Masculino , Distribución Aleatoria , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Tetragastrina/administración & dosificación , Tetragastrina/farmacología , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
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.
Asunto(s)
Fármacos del Sistema Nervioso Autónomo/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Tetragastrina/farmacología , Análisis de Varianza , Electrocardiografía , Genotipo , Humanos , Masculino , PánicoRESUMEN
The anxiolytic effects of GB-115, a retroanalogue of cholecystokinin-4, administered orally to outbred and inbred animals with different level of emotionality, were studied in the open field test and elevated plus-maze test. The anxiolytic effect of talanax was observed in outbred mice (0.1-0.5 mg/kg) and in inbred BALB/c mice (0.1 and 5.0 mg/kg) in the open field test. GB-115 increased the time of entries into open arms in outbred rats (0.5-0.7 mg/kg) and in BALB/c mice (0.1 mg/kg). These data confirmed the dependence of GB-115 effect on the phenotype of emotional stress response and demonstrated a shift of anxiolytic doses of the preparation from 0.006-0.100 mg/kg in intraperitoneal administration to 0.1-5.0 mg/kg in oral treatment.
Asunto(s)
Ansiolíticos/farmacología , Colecistoquinina/farmacología , Dipéptidos/farmacología , Estrés Psicológico/tratamiento farmacológico , Tetragastrina/farmacología , Administración Oral , Animales , Conducta Animal/efectos de los fármacos , Colecistoquinina/análogos & derivados , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , RatasRESUMEN
The conformational analysis with 1H NMR spectroscopy method in solution and the structure-activity relationship study of a series sterically restricted analogs allowed to detect the possible biologically active conformation of N-(6-phenylhexanoyl)glycyl-tryptophan amide (GB-115), a highly active dipeptide cholecystokinin-4 analog with anxiolytic activity. The structure-activity relationship study of GB-115 and the series of its' glycine- and proline-containing analogs with different C-terminal substitute detected the anxiolytic activity of compounds with beta-turn like conformation and inactivity of compounds with gamma-turn like conformation. So, the GB-115 biologically active conformation is beta-turn. The results of nuclear Overhauser effect study permitted to qualify the betaII-turn conformation as GB-115 biologically active conformation. The following synthesis of sterically restricted GB-115 analogs (2S)-2-{(3R)-3-[(6-phenylhexanoyl)amino]-2-oxopyrrolidin-1-yl}-3-(1H-indol-3-yl)propionic acid ethyl ester, N-(6-phenylhexanoyl)glycyl-N(alpha)(methyl)-tryptophan ethyl ester, (2S)-2-[10,11-dihydro-5H-dibenzo[b,f] azepin-5-carbonyl)-amino]-3-(1H-indol-3-yl)propionic acid methyl ester and (2S)-2-[({3-[(ethoxycarbonyl)amino]-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl}carbonyl)amino]-3-(1H-indol-3-yl)propionic acid methyl ester confirmed the estimated type of GB-115 biologically active conformation.
Asunto(s)
Ansiedad/tratamiento farmacológico , Dipéptidos/química , Relación Estructura-Actividad , Tetragastrina/química , Animales , Ansiolíticos/química , Ansiolíticos/farmacología , Ansiedad/patología , Dipéptidos/síntesis química , Dipéptidos/farmacología , Glicina/química , Humanos , Espectroscopía de Resonancia Magnética , Prolina/química , Estructura Secundaria de Proteína , Ratas , Tetragastrina/análogos & derivados , Tetragastrina/farmacología , Triptófano/químicaRESUMEN
Cholecystokinin-tetrapeptide (CCK-4)-induced panic attacks are reportedly attenuated by effective treatment with antipanic antidepressants in patients with panic disorder, but in healthy volunteers such effects are not well studied. The aim of this study was to assess the effect of 6-week treatment with an SSRI escitalopram on CCK-4-induced symptoms in healthy volunteers, who previously responded with a panic attack to CCK-4 challenge. A total of 18 healthy subjects (10 males and eight females, mean age 22.5 ± 5.8) received a 6-week treatment with escitalopram (10 mg/day) and placebo followed by CCK-4 challenge (50 µg) in a double-blind crossover design. The panic rate was 67% after treatment with escitalopram and 56% after treatment with placebo (p = 0.7). Thus, the results showed a significant reduction in CCK-4-induced panic rates without significant differences between escitalopram and placebo conditions. There were no significant effects of either treatment on any other variable of anxiety or cardiovascular indices. Secondary analysis showed no effect of gender or 5-HTTLPR polymorphism on response to CCK-4 challenge. This study demonstrated that in contrast to the findings in patients with panic disorder, in CCK-4-sensitive healthy volunteers the treatment with an antipanic SSRI did not cause a reduction of CCK-4-induced panic attacks beyond the effect of placebo. The mechanisms behind this discrepancy and the reasons of the decrease in sensitivity to CCK-4 challenge on repeated administration remain to be clarified in future studies.
Asunto(s)
Citalopram/farmacología , Trastorno de Pánico/inducido químicamente , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Tetragastrina/antagonistas & inhibidores , Tetragastrina/farmacología , Adulto , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genéticaRESUMEN
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Asunto(s)
Trastorno de Pánico/fisiopatología , Lactato de Sodio/farmacología , Tetragastrina/farmacología , Adulto , Estudios de Casos y Controles , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastorno de Pánico/inducido químicamenteRESUMEN
Recent investigations suggest that genes that confer risk for panic disorder (PD) may moderate response to panicogenic agents in healthy volunteers. Given the potential role of the central cholecystokinin receptor (CCKBR) (CT) polymorphism alleles 26 and 27 in PD, the present study attempted to discern if these alleles moderated panicogenic sensitivity to the CCKBR agonist, CCK-tetrapeptide (CCK-4), in healthy volunteers. The study group consisted of 92 men and women with no personal or family history of psychiatric illness. Participants provided blood samples for genotyping of the CCKBR alleles and they received a 25 µg bolus injection of CCK-4. Behavioral, cardiovascular and hormonal responses to the peptide were assessed and analyzed with adjusted linear regression models. Carriers of the CCKBR alleles tended to have higher levels of pre-challenge anxiety and significantly higher levels of anxiety sensitivity and introversion than those without the alleles. However, they did not exhibit an enhanced panicogenic response to CCK-4. Overall, our findings do not demonstrate a role of these alleles in modulating CCK-4's panicogenicity. The significant association between the risk alleles and anxiety-related personality traits is intriguing and further exploration of this association is merited.
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacología , Receptor de Colecistoquinina B/genética , Tetragastrina/farmacología , Adulto , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Humanos , Masculino , Trastorno de Pánico/inducido químicamente , Trastorno de Pánico/genética , Trastorno de Pánico/psicología , Polimorfismo Genético , Receptor de Colecistoquinina B/agonistas , Factores de Riesgo , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
The anorexigenic effect of cholecystokinin (CCK) is well documented in mammals, but documentation in neonatal chicks is limited. Thus, the present study investigated the mechanism underlying the anorexigenic effect of CCK in neonatal chicks. Intraperitoneal (IP) injection of sulfated CCK(26-33) (CCK8S) significantly decreased food intake in chicks at 60 and 300 nmol/kg. Non-sulfated CCK(26-33) (CCK8) also significantly decreased food intake, but its anorexigenic effect was observed only at the highest dose (300 nmol/kg) and short-lived. However, CCK(30-33) (CCK4) had no effect on food intake. Also, the intracerebroventricular (ICV) injection of CCK8S (0.2 and 1 nmol) significantly decreased food intake in chicks. Similar to IP administration, the anorexigenic effect of CCK8 was weak and CCK4 did not affect food intake. IP and ICV injections of CCK8S caused conditioned aversion and increased plasma corticosterone concentrations, suggesting that their anorexigenic effects might be related to stress and/or malaise. This might be true in ICV-injected CCK8S because co-injection of astressin, a corticotropin-releasing hormone receptor antagonist, tended to attenuate the effect of CCK8S. The present study revealed that N-terminal amino acids and the sulfation of Tyr are important for the anorexigenic effect of CCK8S after IP and ICV administered in chicks. Additionally, the effect of central CCK8S might be related to stress and/or malaise.
Asunto(s)
Depresores del Apetito/farmacología , Pollos/fisiología , Ingestión de Alimentos/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Sincalida/análogos & derivados , Animales , Animales Recién Nacidos , Depresores del Apetito/administración & dosificación , Reacción de Prevención/efectos de los fármacos , Condicionamiento Psicológico/efectos de los fármacos , Corticosterona/sangre , Hormona Liberadora de Corticotropina/farmacología , Relación Dosis-Respuesta a Droga , Inyecciones Intraperitoneales , Inyecciones Intraventriculares , Locomoción/efectos de los fármacos , Masculino , Fragmentos de Péptidos/farmacología , Estimulación Luminosa , Sincalida/administración & dosificación , Sincalida/farmacocinética , Tetragastrina/farmacología , Factores de TiempoRESUMEN
OBJECTIVES: Peripheral administration of the cholecystokinin (CCK) receptor agonist CCK-4 generates panic and activates the hypothalamic-pituitary-adrenal (HPA) axis. Direct effects at the pituitary and CCK-HPA interactions at higher regulatory sites have been suggested. According to preliminary data, ACTH response to CCK receptor agonists may differ from its response to exogenous CRH by its resistance to cortisol feedback inhibition. To further explore this resistance and to better characterize CCK-4 sites of action, the effects of different glucocorticoid pretreatments on CCK-4-induced panic were compared. METHODS: Using a double-blind placebo-controlled design we pretreated healthy males with either dexamethasone (peripheral action) or hydrocortisone (central-peripheral action) each followed by a CCK-4 challenge. Blood levels of ACTH and cortisol were analyzed and panic symptoms were assessed. RESULTS: We found a blunted response of ACTH release following CCK-4 injection only after hydrocortisone pretreatment. Dexamethasone however did not affect CCK-4-induced ACTH release relative to baseline. In contrast to dexamethasone, hydrocortisone reduced the severity of CCK-4-induced panic as measured by the Acute Panic Inventory on a trend level. CONCLUSIONS: Findings suggest that CCK-4-induced stress hormone release seems susceptible to cortisol-feedback inhibition and argues for a suprapituitary site of CCK action. Effects on panic anxiety were weak but congruent with studies showing that CCK-4-induced HPA axis inhibition is accompanied by a reduction of anxiety after CCK-4.
Asunto(s)
Antiinflamatorios/farmacología , Dexametasona/farmacología , Hidrocortisona/farmacología , Trastorno de Pánico/inducido químicamente , Trastorno de Pánico/tratamiento farmacológico , Tetragastrina/farmacología , Hormona Adrenocorticotrópica/sangre , Adulto , Análisis de Varianza , Método Doble Ciego , Humanos , Hidrocortisona/sangre , Masculino , Escalas de Valoración Psiquiátrica/estadística & datos numéricos , Índice de Severidad de la EnfermedadRESUMEN
The function of brush cells is obscure, but recent cytochemical studies indicate that rat bile duct brush cells secrete NaHCO(3). The aim of this study was to determine the quantitative distribution of brush cells at 16 sites of the rat gastrointestinal tract and to investigate the role of NaHCO(3) secretion at these sites. Specimens of 16 sites of the gastrointestinal tracts of three female Long-Evans rats were fixed in a periodate-lysine-paraformaldehyde solution. Frozen sections were stained with the anti-cytokeratin 18 antibody, a selective marker for brush cells. The numbers of brush cells were counted from photographs. The percentages of brush cells in the epithelium at the 16 sites were gastric groove, 32.3%; corpus adjacent to the gastric groove, 2.5%; corpus, 0.4%; antrum, 0.4%; duodenum adjacent to the pyloric ring, 2.3%; proximal duodenum, 0%; duodenum facing the bile duct orifice, 0%; distal duodenum, 0.2%; proximal jejunum, 0.1%; transitional site between the jejunum and the ileum, 0.1%; distal ileum, Peyer's patch dome, 1.5%; and the villi, 0.4%; caecum, 2.1%; proximal colon, 0.2%; middle colon, 0.1%; distal colon, 0.1%; and rectum, 0.1%. We concluded that the population of brush cells is high in the gastric groove, the duodenum adjacent to the pyloric ring, and the caecum, where NaHCO(3) is postulated to neutralize gastric HCL or organic acids produced by enteric bacteria. The brush cell population is low in the duodenum and jejunum, which receive bile and pancreatic juice.
Asunto(s)
Células Epiteliales/ultraestructura , Tracto Gastrointestinal/citología , Microvellosidades/metabolismo , Bicarbonato de Sodio/metabolismo , Animales , Recuento de Células , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Células Epiteliales/citología , Células Epiteliales/metabolismo , Femenino , Mucosa Gástrica/citología , Mucosa Gástrica/metabolismo , Fármacos Gastrointestinales/farmacología , Tracto Gastrointestinal/metabolismo , Tracto Gastrointestinal/ultraestructura , Concentración de Iones de Hidrógeno , Mucosa Intestinal/citología , Mucosa Intestinal/metabolismo , Queratina-18/metabolismo , Ratas , Ratas Long-Evans , Tetragastrina/farmacologíaRESUMEN
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.
Asunto(s)
Ansiolíticos/farmacología , Ansiedad/inducido químicamente , Ansiedad/fisiopatología , Lorazepam/administración & dosificación , Pánico/efectos de los fármacos , Tetragastrina/efectos adversos , Adulto , Ansiolíticos/administración & dosificación , Trastornos de Ansiedad/fisiopatología , Atención/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/fisiopatología , Estudios Cruzados , Giro del Cíngulo/efectos de los fármacos , Giro del Cíngulo/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Lorazepam/farmacología , Imagen por Resonancia Magnética , Masculino , Pánico/fisiología , Trastorno de Pánico/inducido químicamente , Trastorno de Pánico/fisiopatología , Escalas de Valoración Psiquiátrica , Tetragastrina/farmacología , Adulto JovenRESUMEN
The effects of GB-115 dipeptide, a retroanalog of endogenous CCK-4, on the behavioral indices in "elevated plus maze" (EPM) test and on the content of biogenic amines in the brain structures after discontinuation of a chronic administration of benzodiazepine (BZ) derivatives phenazepam (2.0 mg/kg, i.p.) and diazepam (4.0 mg/kg, i.p.) have been studied in outbred and inbred MR/MNRA rats. It is established that, in 24-48 h following BZ withdrawal, GB-115 dipeptide administered in doses of 0.1 and 0.5 mg/kg, i.p., produced an anxiolytic effect in all animals, which was manifested by increasing the stay time and number of entries in EPM. In the striatum of outbred rats, GB-115 increased DOPAC (+25%) and DA (+31.6%) levels that were decreased during diazepam withdrawal syndrome. The obtained results showed the GB-115 efficiency in attenuating the anxiety caused by BZ withdrawal.
Asunto(s)
Ansiolíticos/farmacología , Trastornos de Ansiedad/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Tranquilizantes/farmacología , Ácido 3,4-Dihidroxifenilacético/análisis , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Animales no Consanguíneos , Trastornos de Ansiedad/metabolismo , Trastornos de Ansiedad/fisiopatología , Benzodiazepinas/farmacología , Diazepam/farmacología , Dipéptidos/farmacología , Modelos Animales de Enfermedad , Dopamina/análisis , Dopamina/metabolismo , Conducta Exploratoria/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratas , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/fisiopatología , Tetragastrina/farmacologíaRESUMEN
Layer 6b in neocortex is a distinct sublamina at the ventral portion of layer 6. Corticothalamic projections arise from 6b neurons, but few studies have examined the functional properties of these cells. In the present study we examined the actions of cholecystokinin (CCK) on layer 6b neocortical neurons using whole-cell patch clamp recording techniques. We found that the general CCK receptor agonist CCK8S (sulfated CCK octapeptide) strongly depolarized the neurons, and this action persisted in the presence of tetrodotoxin, suggesting a postsynaptic site of action. The excitatory actions of CCK8S were mimicked by the selective CCK(B) receptor agonist CCK4, and attenuated by the selective CCK(B) receptor antagonist L365260, indicating a role for CCK(B) receptors. Voltage-clamp recordings revealed that CCK8S produced a slow inward current associated with a decreased conductance with a reversal potential near the K(+) equilibrium potential. In addition, intracellular cesium also blocked the inward current, suggesting the involvement of a K(+) conductance, likely K(leak). Our data indicate that CCK, acting via CCK(B) receptors, produces a long-lasting excitation of layer 6b neocortical neurons, and this action may play a critical role in modulation of corticothalamic circuit activity.
Asunto(s)
Potenciales de Acción/fisiología , Colecistoquinina/metabolismo , Neuronas/metabolismo , Receptor de Colecistoquinina B/metabolismo , Corteza Somatosensorial/metabolismo , Tálamo/metabolismo , Potenciales de Acción/efectos de los fármacos , Animales , Animales Recién Nacidos , Benzodiazepinonas/farmacología , Colecistoquinina/análogos & derivados , Colecistoquinina/farmacología , Vías Eferentes/citología , Vías Eferentes/efectos de los fármacos , Vías Eferentes/metabolismo , Neuronas/citología , Neuronas/efectos de los fármacos , Técnicas de Cultivo de Órganos , Técnicas de Placa-Clamp , Fragmentos de Péptidos/farmacología , Compuestos de Fenilurea/farmacología , Canales de Potasio/efectos de los fármacos , Canales de Potasio/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor de Colecistoquinina B/efectos de los fármacos , Corteza Somatosensorial/citología , Corteza Somatosensorial/efectos de los fármacos , Tetragastrina/farmacología , Tálamo/citología , Tálamo/efectos de los fármacosRESUMEN
Experimental panic induction with cholecystokinin tetrapeptide (CCK-4) is considered as a suitable model to investigate the pathophysiology of panic attacks. While only a few studies investigated the brain activation patterns following CCK-4, no data are available on the putative involvement of the amygdala in the CCK-4 elicited anxiety response. We studied the functional correlates of CCK-4-induced anxiety in healthy volunteers by means of functional magnetic resonance imaging (fMRI) and region of interest (ROI) analysis of the amygdala. Sixteen healthy volunteers underwent challenge with CCK-4 compared with placebo in a single-blind design. Functional brain activation patterns were determined for the CCK-4-challenge, the placebo response and anticipatory anxiety (AA). CCK-4-induced anxiety was accompanied by a strong and robust activation (random effects analysis, P < 0.00001, uncorrected for multiple testing) in the ventral anterior cingulate cortex (ACC), middle and superior frontal gyrus, precuneus, middle and superior temporal gyrus, occipital lobe, sublobar areas, cerebellum, and brainstem. In contrast, random effects group analysis for placebo and AA using the same level of significance generated no significant results. Using a more liberal level of significance, activations could be observed in some brain regions such as the dorsal part of the ACC during AA (random effects analysis, P < 0.005). Overall functional responses did not differ between panickers and nonpanickers. Only 5 of 11 subjects showed strong amygdala activation. However, ROI analysis pointed towards higher scores in fear items in these subjects. In conclusion, while overall brain activation patterns are not related to the subjective anxiety response to CCK-4, amygdala activation may be involved in the subjective perception of CCK-4-induced fear.
Asunto(s)
Encéfalo/fisiopatología , Red Nerviosa/fisiopatología , Trastorno de Pánico/fisiopatología , Adulto , Amígdala del Cerebelo/anatomía & histología , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/fisiopatología , Ansiedad/inducido químicamente , Ansiedad/fisiopatología , Encéfalo/anatomía & histología , Encéfalo/efectos de los fármacos , Mapeo Encefálico , Miedo/efectos de los fármacos , Miedo/fisiología , Giro del Cíngulo/anatomía & histología , Giro del Cíngulo/efectos de los fármacos , Giro del Cíngulo/fisiopatología , Humanos , Sistema Límbico/anatomía & histología , Sistema Límbico/efectos de los fármacos , Sistema Límbico/fisiopatología , Imagen por Resonancia Magnética , Masculino , Red Nerviosa/anatomía & histología , Red Nerviosa/efectos de los fármacos , Trastorno de Pánico/inducido químicamente , Tetragastrina/farmacología , Adulto JovenRESUMEN
Recent animal studies consistently confirm the involvement of brain-derived neurotrophic factor (BDNF) in the regulation of anxiety-related behaviours. The role of BDNF in human anxiety has been less investigated. The aim of our study was to examine the association between serum BDNF levels and panic/anxiety responses to cholecystokinin-tetrapeptide (CCK-4) challenge in healthy subjects. BDNF concentrations were detected in serum samples of 37 male and female volunteers before and 120 min after CCK-4 injection. The baseline levels of serum BDNF did not predict the occurrence of CCK-4-induced panic attacks or intensity of panic symptoms and did not significantly change 2 h after the challenge. BDNF serum concentrations 120 min after provocation did not differentiate panickers from non-panickers; however, the subjects reporting stronger anxiety response showed higher levels of BDNF than those with mild anxiety. The anxiety net increase on the Visual Analogue Scale, but not severity of panic symptoms, significantly and positively correlated with the change in BDNF concentration from baseline values. This is the first challenge study to demonstrate a possible impact of BDNF on human anxiety. Our findings suggest a general involvement of BDNF in the regulation of anxiety rather than a specific role of BDNF in disposition to panic attacks.
Asunto(s)
Ansiedad/inducido químicamente , Ansiedad/metabolismo , Factor Neurotrófico Derivado del Encéfalo/sangre , Pánico/fisiología , Tetragastrina/farmacología , Adolescente , Adulto , Femenino , Humanos , Masculino , Pánico/efectos de los fármacos , Trastorno de Pánico/inducido químicamente , Trastorno de Pánico/metabolismoRESUMEN
In order to elucidate the impact of psychological factors on panic severity the correlation between baseline anxiety and panic response to cholecystokinin-tetrapeptide (CCK-4), an established model of human anxiety, was investigated in 33 healthy volunteers. Baseline anxiety was assessed with the State-Trait-Anxiety-Inventory (STAI). Trait and state anxiety did not differ between panickers and nonpanickers nor were they correlated with panic severity. In conclusion, psychological factors are not major determinants for the subjective panic response to CCK-4 thus emphasising the importance of neurobiological factors.
Asunto(s)
Trastornos de Ansiedad/diagnóstico , Trastornos de Ansiedad/psicología , Encéfalo/fisiopatología , Trastorno de Pánico/diagnóstico , Trastorno de Pánico/psicología , Tetragastrina/farmacología , Adulto , Ansiedad , Trastornos de Ansiedad/inducido químicamente , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Causalidad , Resistencia a Medicamentos , Miedo/efectos de los fármacos , Miedo/fisiología , Humanos , Masculino , Pruebas Neuropsicológicas , Trastorno de Pánico/inducido químicamente , Valor Predictivo de las Pruebas , Tetragastrina/metabolismoRESUMEN
INTRODUCTION: Installation, operation and performance qualifications were performed on a test system for respiratory monitoring. METHODS: For performance qualification, conscious dogs received saline (0.2 mL/kg, iv, n=12), albuterol (100 microg/kg, inhalation, n=5), methacholine (2.0 and 8.0 microg/kg, iv, n=8) and remifentanil (4.0 microg/kg, iv, n=7). Following anesthesia with propofol infusion, dogs received saline (iv, n=15), albuterol (100 microg/kg, inhalation, n=8), methacholine (8.0 microg/kg, iv, n=8), remifentanil (4.0 microg/kg, iv, n=7), and cholecystokinine tetrapeptide (CCK-4) (10 microg/kg, iv, n=7) and were exposed to hypoxic gas mixture (10% oxygen) (n=12). RESULTS: Saline had no significant respiratory effect. Albuterol increased tidal volume (TV) (+28%, p<0.05) and minute ventilation (MV) (+96%, p<0.01) in conscious dogs. In anesthetized dogs, MV was significantly increased (+23%, p<0.05) but the difference was not statistically significant for TV and respiratory rate (RR). Methacholine at 2.0 microg/kg increased MV (+45%, p<0.01) in conscious animals while 8.0 microg/kg increased RR (+66%, p<0.01), TV (+24%, p<0.05) and MV (+88%, p<0.05). In anesthetized dogs, methacholine increased RR (+51%, p<0.05), MV (+34%, p<0.05), lung elastance (+36.9%, p<0.01), and resistance (+45.8%, p<0.01). Remifentanil decreased MV in conscious dogs (-68%, p<0.01) while transient apnea was observed in all anesthetized dogs. CCK-4 increased RR (+328%, p<0.01) and MV (+127%, p<0.05) and decreased TV (-58%, p<0.01). Exposure to hypoxic gas mixture increased MV and RR (p<0.01). Baseline MV was lower (p<0.05) in anesthetized than in conscious dogs. DISCUSSION: Arterial blood gas values, particularly SaO(2), presented a limited sensitivity to detect any ventilation disturbance, but allowed confirmation of both ventilatory compensatory phenomenon (when present) and initial pharmacologic drug effect. These results also highlight the greater sensitivity of the conscious model when compared to anesthetized dogs.