RESUMEN
The vigilance-enhancing agent modafinil has neuroprotective properties: it prevents striatal ischemic injury, nigrostriatal pathway deterioration after partial transsection and intoxication with 1-methyl-1,2,3,6-tetrahydropyridine. The present study determines the protective effects of modafinil in the marmoset 1-methyl-1,2,3,6-tetrahydropyridine Parkinson model on behavior and on monoamine levels. Twelve marmoset monkeys were treated with a total dose of 6 mg/kg 1-methyl-1,2,3,6-tetrahydropyridine. Simultaneously, six animals received a daily oral dose of modafinil (100 mg/kg) and six animals received vehicle for 27 days. Behavior was observed daily and the locomotor activity, hand-eye coordination, small fast movements, anxiety-related behavior and startle response of the animals were tested twice a week for 3 weeks. Modafinil largely prevented the 1-methyl-1,2,3,6-tetrahydropyridine-induced change in observed behavior, locomotor activity, hand-eye coordination and small fast movements, whereas the vehicle could not prevent the devastating effects of 1-methyl-1,2,3,6-tetrahydropyridine. Dopamine levels in the striatum of the vehicle+1-methyl-1,2,3,6-tetrahydropyridine-treated animals were reduced to 5% of control levels, whereas the dopamine levels of the modafinil+1-methyl-1,2,3,6-tetrahydropyridine-treated animals were reduced to 41% of control levels. The present data suggest that modafinil prevents decrease of movement-related behavior and dopamine levels after 1-methyl-1,2,3,6-tetrahydropyridine intoxication and can be an efficaceous pharmacological intervention in the treatment of Parkinson's disease.
Asunto(s)
Nivel de Alerta/efectos de los fármacos , Compuestos de Bencidrilo/farmacología , Dopamina/metabolismo , Actividad Motora/efectos de los fármacos , Destreza Motora/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Trastornos Parkinsonianos/fisiopatología , Desempeño Psicomotor/efectos de los fármacos , Reflejo de Sobresalto/efectos de los fármacos , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/antagonistas & inhibidores , Administración Oral , Animales , Callithrix , Cuerpo Estriado/efectos de los fármacos , Humanos , Masculino , ModafiniloRESUMEN
Corticotropin-releasing factor (CRF) acts through CRF 1 and CRF 2 receptors (CRF1, CRF2). To test the hypothesis that CRF controls the expression of these receptors in a brain site- and receptor-type specific manner, we studied CRF1 mRNA and CRF2 mRNA expressions in mice with central CRF over-expression (CRF-OE) and using in situ hybridization. CRF1 and CRF2 mRNAs appear to be differentially distributed across the brain. The brain structures expressing the receptors are the same in wild-type (WT) and in CRF-OE mice. We therefore conclude that chronically elevated CRF does not induce or inhibit expression of these receptors in structures that normally do not or do, respectively, show these receptors. However, from counting cell body profiles positive for CRF1 and CRF2 mRNAs, clear differences appear in receptor expression between CRF-OE and WT mice, in a brain-structure-specific fashion. Whereas some structures do not differ, CRF-OE mice exhibit remarkably lower numbers of CRF1 mRNA-positive profiles in the subthalamic nucleus (-38.6%), globus pallidus (-31.5%), dorsal part of the lateral septum (-23.5%), substantia nigra (-22,8%), primary somatosensory cortex (-18.9%) and principal sensory nucleus V (-18.4%). Furthermore, a higher number of CRF2 mRNA-positive profiles are observed in the dorsal raphe nucleus (+32.2%). These data strongly indicate that central CRF over-expression in the mouse brain is associated with down-regulation of CRF1 mRNA and up-regulation of CRF2 mRNA in a brain-structure-specific way. On the basis of these results and the fact that CRF-OE mice reveal a number of physiological and autonomic symptoms that may be related to chronic stress, we suggest that CRF1 in the basal nuclei may be involved in disturbed information processing and that CRF2 in the dorsal raphe nucleus may play a role in mediating stress-induced release of serotonin by CRF.
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Encéfalo/fisiología , Hormona Liberadora de Corticotropina/genética , Receptores de Hormona Liberadora de Corticotropina/genética , Animales , Animales Modificados Genéticamente , Hibridación in Situ , Ratones , ARN Mensajero/genéticaRESUMEN
In mammals, stress exposure is frequently associated with an elevated body temperature ['emotional fever', stress-induced hyperthermia (SIH)]. Rectal measurement of body core temperature of the mouse induces a rise of 1-1.5 degrees C over a 10- to 15-min time interval. This phenomenon has been exploited to design a specific test for measuring stress-induced hyperthermia: the singly-housed SIH paradigm in mice. In the present experiments, changes in body temperature and corticosterone levels were studied 10, 30, 60, 90 and 120 min after the first insertion of the rectal probe. In addition, changes in patterns of neural activation, as observed after immunostaining for Fos-immunoreactivity (Fos-IR), were studied in the brains of animals perfused at times 0, 60 or 120 min. Our results show that SIH and corticosterone levels have their peak values between 10 and 30 min and are no longer different from control values after 60 min. Patterns of Fos-IR have been studied in 11 brain areas, of which 2 brain areas (anterodorsal preoptic and periolivary nuclei) showed a continuing rise in Fos-IR after 60 and 120 min, while six nuclei, mostly hypothalamic and septal, showed a peak induction of Fos-IR after 60 min. In three brain areas, no consistent changes in Fos-IR could be observed. The authors conclude that the changes observed in the patterns of Fos-IR, after application of the singly-housed SIH-test in mice, reflect the effects of both the stressor application and the ensuing thermoregulatory responses. The role of each activated brain area in either one of these effects is discussed in view of data available from the literature.
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Temperatura Corporal/fisiología , Corticosterona/metabolismo , Fiebre/fisiopatología , Genes fos/fisiología , Estrés Psicológico/fisiopatología , Animales , Química Encefálica/fisiología , Fiebre/etiología , Fiebre/genética , Inmunohistoquímica , Masculino , Ratones , Neuronas/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Radioinmunoensayo , Estrés Psicológico/complicaciones , Estrés Psicológico/genéticaRESUMEN
Serotonin(1A) (5-HT(1A)) receptors are involved in anxiety. This study focuses on the role of genetic factors on the anxiety-related effects of 5-HT(1A) receptor stimulation using both a within subject design. The effects of 5-HT(1A) receptor activation were studied in high- and low-anxiety mice (129S6/SvEvTac (S6) and C57BL/6J (B6), respectively) in behavioral and physiological anxiety-related assays. These two strains were also selected because they are frequently used in gene-targeting studies. Mice were treated with the selective 5-HT(1A) receptor agonist flesinoxan (0-0.3-1.0-3.0 mg/kg s.c.) and tested in either the open-field activity test, the light-dark exploration test, or the stress-induced hyperthermia paradigm. Flesinoxan unexpectedly increased anxiety, but also decreased activity on several behavioral measures in B6 mice. Flesinoxan produced only minimal effects in the behavioral tests in the high-anxiety S6 strain. In contrast, the physiological hyperthermia response showed anxiolytic-like effects of flesinoxan in both strains. Our data indicate that the role of 5-HT(1A) receptor activation on anxiety-related responses is dependent on genetic background and selected paradigm used to assess anxiety. These findings indicate that it is critical to use a multi-level approach to develop mouse models for human diseases. In addition, the implication of such findings for studies on genetically modified mice is discussed.
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Ansiedad/tratamiento farmacológico , Modelos Animales de Enfermedad , Piperazinas/uso terapéutico , Animales , Ansiedad/genética , Oscuridad , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Iluminación , Masculino , Ratones , Ratones Endogámicos C57BL , Piperazinas/farmacología , Especificidad de la EspecieRESUMEN
Over the last decade, many genetically modified mice have been developed as models for psychiatric diseases such as anxiety. Limited availability of such mutant mice highlights the importance of studying the possibility of repeatedly testing the same individuals. We tested mice four times with 1-week intervals with the same dose of the 5-HT(1A) receptor agonist flesinoxan (0-0.3-1.0-3.0 mg/kg s.c.) in three anxiety-related paradigms: light-dark exploration, open-field activity and stress-induced hyperthermia. The two inbred strains studied were the highly anxious 129S6/SvEvTac (S6) and low-anxiety C57BL/6J (B6) mice. The results indicate that the effects of repeated testing were relatively mild. B6 mice showed some mild habituation in the open-field test when treated with vehicle, whereas S6 mice developed reduced initial activity in the light-dark box after drug treatment. In contrast, responses to flesinoxan treatment were strong and highly consistent for most parameters. In the open-field and light-dark tests, B6 mice showed reduced activity and anxiogenic-like behavioral responses, whereas S6 mice were minimally affected. Anxiolytic-like responses were found in both strains in the stress-induced hyperthermia paradigm. We conclude that B6 and S6 mice can be tested repeatedly with agents such as 5-HT(1A) receptor agonists with 1-week intervals in the three paradigms tested.
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Ansiedad/tratamiento farmacológico , Modelos Animales de Enfermedad , Piperazinas/uso terapéutico , Animales , Ansiedad/genética , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Fiebre/inducido químicamente , Masculino , Ratones , Ratones Endogámicos C57BL , Piperazinas/farmacología , Especificidad de la EspecieRESUMEN
BACKGROUND: It has been suggested that the light-enhanced startle paradigm (LES) is an animal model for anxiety, because of the unconditioned and nonspecific cue and the long-term effect. In contrast, the fear-potentiated startle (FPS) is suggested to model fear. In the present study, we assessed in detail the time course of LES and FPS and investigated whether corticotropin-releasing hormone (CRH) is differentially involved in these two models. METHODS: In experiment 1, the amplitude of the startle response was tracked in the presence of the light and after light offset, in both models. In experiment 2, the effects of intracerebroventricular administration of the CRH-receptor antagonist alpha-helical CRH (0, 1, 5, and 25 microg) on LES and FPS were studied. RESULTS: In LES, light onset resulted in a long-lasting potentiation of the startle response and a slow return to baseline after light offset. In FPS, the potentiation of the startle response returned to baseline almost immediately after light offset. Alpha-helical CRH reduced the potentiation in LES at the 5-microg dose but not at 25 microg. In FPS, alpha-helical CRH had no effect. CONCLUSIONS: The results show that the time course of LES is markedly different from that of FPS, which together with the differences in eliciting stimuli suggest that they model anxiety and fear, respectively. Moreover, the results suggest that CRH is involved in LES and not in FPS.
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Ansiedad/metabolismo , Hormona Liberadora de Corticotropina/farmacología , Miedo , Antagonistas de Hormonas/farmacología , Luz , Reflejo de Sobresalto/efectos de los fármacos , Estimulación Acústica , Animales , Conducta Animal , Condicionamiento Clásico , Oscuridad , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Inyecciones Intraventriculares/métodos , Masculino , Estimulación Luminosa , Ratas , Ratas Wistar , Reflejo de Sobresalto/fisiologíaRESUMEN
Chronically elevated levels of corticotropin-releasing factor (CRF) in transgenic mice overexpressing CRF in the brain (CRF-OE) appear to be associated with alterations commonly associated with major depressive disorder, as well as with sensorimotor gating deficits commonly associated with schizophrenia. In the present study, we tested the hypothesis that antipsychotics may be effective in normalizing prepulse inhibition (PPI) of acoustic startle in CRF-OE mice, which display impaired sensorimotor gating compared to wild-type (WT) mice. The typical antipsychotic haloperidol and atypical antipsychotic risperidone improved PPI in the CRF-OE mice, but were ineffective in WT mice. The atypical antipsychotic clozapine did not influence PPI in CRF-OE mice, but reduced gating in WT mice. This effect of clozapine in the CRF-OE mice may thus be regarded as a relative improvement, consistent with the observed effect of haloperidol and risperidone. As expected, the anxiolytic, nonantipsychotic chlordiazepoxide was devoid of any effect. All four compounds dose-dependently reduced the acoustic startle response irrespective of genotype. These results indicate that antipsychotic drugs are effective in improving startle gating deficits in the CRF-OE mice. Hence, the CRF-OE mouse model may represent an animal model for certain aspects of psychotic depression, and could be a valuable tool for research addressing the impact of chronically elevated levels of CRF on information processing.
Asunto(s)
Antipsicóticos/farmacología , Hormona Liberadora de Corticotropina/biosíntesis , Inhibición Psicológica , Reflejo de Sobresalto/efectos de los fármacos , Estimulación Acústica , Animales , Conducta Animal , Peso Corporal/efectos de los fármacos , Hormona Liberadora de Corticotropina/genética , Depresión , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos , Ratones Transgénicos , Reflejo Acústico/efectos de los fármacos , Reflejo de Sobresalto/fisiología , Estimulación QuímicaRESUMEN
Previous studies with mice lacking 5-HT(1A) (1AKO) and 5-HT(1B) (1BKO) receptors in hippocampus-dependent learning and memory paradigms, suggest that these receptors play an important role in learning and memory, although their precise role is unclear. In the present study, 1AKO and 1BKO mice were studied in operant behavioural paradigms of decision making and response inhibition, to further study the putative involvement of these receptors in prefrontal cortex-dependent learning and memory. Moreover, because 1AKO mice have been shown to exhibit an antidepressant-like phenotype and 1BKO mice to be more impulsive in ethological studies, mice were trained in a differential-reinforcement-of-low-rates (DRL) procedure. Overall, results indicate that 1AKO and 1BKO mice display subtle differences in operant paradigms of decision making and response inhibition compared to wild type (WT) mice. In addition, when responding under a DRL 36-s schedule had stabilised, 1BKO mice showed a phenotype indicative of increased impulsivity, whereas 1AKO mice did not differ from WT mice. In conclusion, 5-HT(1B) receptors appear to play an important role in impulsivity and a minor role in prefrontal cortex-dependent learning and memory as shown by the results obtained in serial reversal learning and extinction. In contrast, 5-HT(1A) receptors appear to be involved in facilitation of autoshaping, but their role in impulsivity and prefrontal cortex-dependent learning and memory appears to be limited.
Asunto(s)
Condicionamiento Operante/fisiología , Receptores de Serotonina/fisiología , Esquema de Refuerzo , Animales , Extinción Psicológica/fisiología , Masculino , Ratones , Ratones Noqueados , Receptor de Serotonina 5-HT1B , Receptores de Serotonina/genética , Receptores de Serotonina 5-HT1 , Aprendizaje Inverso/fisiologíaRESUMEN
When mammals, including man, are confronted with a stressful event, their core body temperature rises, stress-induced hyperthermia. In mice, the stress-induced hyperthermia procedure has been developed to measure antistress or anxiolytic-like effects of psychoactive drugs. Group-housed and singly housed versions of the stress-induced hyperthermia generate comparable results. Because the number of animals needed to perform an experiment is much lower in the singly housed versus the group-housed procedure, the former is the test of choice for pharmacological testing. A typical stress-induced hyperthermia test starts with an injection 60 min before the first rectal temperature measurement (T(1)), followed by a second temperature measurement (T(2)) 10-15 min later. The difference DeltaT (=T(2)-T(1)) is the stress-induced hyperthermia. The procedure also measures the intrinsic activity of drugs on the basal body temperature and DeltaT is relatively independent from the intrinsic temperature effects of drugs. Anxiolytic drugs (benzodiazepines, 5-HT(1A) receptor agonists, alcohol) reduce DeltaT suggestive of anxiolytic-like effects. Because the parameter measured for anxiety in the stress-induced hyperthermia procedure is not dependent on locomotor activity, like in almost all other anxiety tests, the stress-induced hyperthermia procedure is an attractive addition to tests in the anxiety field. Because the stress-induced hyperthermia is also present with a comparable pharmacological profile in females, this procedure has a wide species and gender validity. The procedure was applied in various genetically modified mice [5-HT(1A) and 5-HT(1B) receptor knockout (KO) mice and corticotropin-releasing hormone overexpressing (CRH-OE) mice] to study phenotypic influences of the various mutations on aspects of anxiety. The stress-induced hyperthermia test in singly housed male and female mice appears a useful and extremely simple test to measure effects of drugs on certain aspects of anxiety or to help to determine phenotypic differences in mutant mice.
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Ansiedad/psicología , Fiebre/psicología , Estrés Fisiológico/psicología , Animales , Ansiolíticos/farmacología , Ansiedad/etiología , Ansiedad/fisiopatología , Temperatura Corporal/efectos de los fármacos , Sistema Endocrino/efectos de los fármacos , Sistema Endocrino/fisiopatología , Fiebre/etiología , Fiebre/fisiopatología , Ratones , Modelos Animales , Receptores de Hormona Liberadora de Corticotropina/efectos de los fármacos , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Receptores de Serotonina/efectos de los fármacos , Estrés Fisiológico/complicaciones , Estrés Fisiológico/fisiopatologíaRESUMEN
Pharmacological experiments have implicated a role for serotonin (5-HT)(1A) receptors in the modulation of anxiety. More recent is the interest in corticotropin-releasing hormone (CRH) system as a potential target for the treatment of anxiety disorders. However, selective pharmacological tools for the CRH system are limited, hampering research in this field. Gene targeting is a relatively new approach to study mechanisms underlying anxiety disorders. 5-HT(1A) receptor knockout (1AKO) mice have been created on three different background strains, and two different lines of mice, overexpressing CRH (CRH-OE), have been generated. In the present review, behavioural and physiological findings reported for 1AKO mice and CRH-OE mice will be reviewed. As behavioural phenotyping is often limited to one or two approach avoidance paradigms, we extended these observations and also tested 1AKO and CRH-OE mice in a conditioned fear paradigm. This paradigm reflects essentially different aspect of anxiety than approach avoidance paradigms. 1AKO mice on a 129/Sv background strain showed similar freezing as wild-type (WT) mice. In CRH-OE mice, less freezing was observed than in the corresponding wild-type mice. The fact that the anxious phenotype of these genetically altered mice seems less clear than initially reported will be discussed. Rather than studying the direct consequences of alterations in the targeted gene, 1AKO and CRH-OE mice seem very valuable to study compensatory processes that seem to have taken place in reaction to life-long changes in gene expression.
Asunto(s)
Ansiedad/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Receptores de Serotonina/genética , Animales , Ansiedad/genética , Ansiedad/psicología , Conducta Animal , Hormona Liberadora de Corticotropina/genética , Modelos Animales de Enfermedad , Ratones , Ratones Noqueados , Receptores de Serotonina/metabolismo , Receptores de Serotonina 5-HT1RESUMEN
To gain a greater insight into the relationship between hyperactivity of the corticotropin-releasing hormone (CRH) system and autonomic and physiological changes associated with chronic stress, we developed a transgenic mouse model of central CRH overproduction. The extent of central and peripheral CRH overexpression, and the amount of bioactive CRH in the hypothalamus were determined in two lines of CRH-overexpressing (CRH-OE) mice. Furthermore, 24 h patterns of body temperature, heart rate, and activity were assessed using radiotelemetry, as well as cumulative water and food consumption and body weight gain over a 7-day period. CRH-OE mice showed increased amounts of CRH peptide and mRNA only in the central nervous system. Despite the presence of the same CRH transgene in their genome, only in one of the two established lines of CRH-OE mice (line 2122, but not 2123) was overexpression of CRH associated with increased levels of bioactive CRH in the hypothalamus, increased body temperature and heart rate (predominantly during the light (inactive) phase of the diurnal cycle), decreased heart rate variability during the dark (active) phase, and increased food and water consumption, when compared with littermate wildtype mice. Because line 2122 of the CRH transgenic mice showed chronic stress-like neuroendocrine and autonomic changes, these mice appear to represent a valid animal model for chronic stress and might be valuable in the research on the consequences of CRH excess in situations of chronic stress.
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Sistema Nervioso Autónomo/fisiología , Hormona Liberadora de Corticotropina/metabolismo , Hipotálamo/metabolismo , Animales , Temperatura Corporal/fisiología , Sistema Nervioso Central/química , Sistema Nervioso Central/fisiología , Hormona Liberadora de Corticotropina/análisis , Frecuencia Cardíaca/fisiología , Hipotálamo/química , Masculino , Ratones , Ratones Transgénicos/inmunología , Ratones Transgénicos/fisiología , Estrés Fisiológico , Regulación hacia Arriba/fisiologíaRESUMEN
5-HT(1A) receptor knockout (KO) mice have been described as more anxious in various anxiety paradigms. Because anxiety is often associated with autonomic changes like elevated body temperature and tachycardia, radiotelemetry was used to study these parameters in wild type (WT) and KO mice in stress-/anxiety-related paradigms. Basal body temperature (BT), heart rate (HR), and their diurnal rhythmicity did not differ between well-adapted WT and KO mice. In a simple stress-test, the Stress-induced Hyperthermia (SIH), injection-stress resulted in an exaggerated stress-response in KO mice. Furthermore, the 5-HT(1A) receptor agonist flesinoxan dose-dependently antagonized SIH and stress-induced tachycardia in WT, but not in KO, mice. In both genotypes, diazepam blocked SIH, but not stress-induced tachycardia. Finally, KO mice displayed an exaggerated stress response in HR and BT to novelty stress; this was supported by behavioral indications of enhanced anxiety. The present findings show that 5-HT(1A) receptor KO mice display a more "anxious-like" phenotype not only at a behavioral, but also at autonomic levels.
Asunto(s)
Ansiedad/fisiopatología , Temperatura Corporal/fisiología , Frecuencia Cardíaca/fisiología , Receptores de Serotonina/fisiología , Análisis de Varianza , Animales , Ansiolíticos/farmacología , Ansiedad/tratamiento farmacológico , Ansiedad/genética , Conducta Animal/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Diazepam/farmacología , Conducta Exploratoria/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Ratones , Ratones Noqueados , Piperazinas/farmacología , Receptores de Serotonina/genética , Receptores de Serotonina 5-HT1 , Estrés FisiológicoRESUMEN
Previous studies in 5-HT(1A) receptor knockout (1AKO) mice on a mixed Swiss Websterx129/Sv (SWx129/Sv) and a pure 129/Sv genetic background suggest a differential gamma-aminobutyric acid (GABA(A))-benzodiazepine receptor complex sensitivity in both strains, independent from the anxious phenotype. To further investigate these discrepancies, various GABA(A)-benzodiazepine receptor ligands were tested in different behavioral paradigms in 1AKO and wild type (WT) mice on a 129/Sv background. 1AKO and WT mice responded comparably to alprazolam, flumazenil, alcohol and pentylenetetrazol as measured in the stress-induced hyperthermia paradigm. In addition, sedative-anesthetic effects of pentobarbital measured via the righting reflex were similar and a selected dose of diazepam exerted similar anxiolytic effects in both genotypes in the elevated plus maze. In conclusion, 1AKO mice on a 129/Sv background have undisturbed GABA(A)-benzodiazepine receptor sensitivity in contrast to those described on a mixed Swiss Websterx129/Sv background. The anxious phenotype of 1AKO mice seems to occur independent of the GABA(A)-benzodiazepine receptor complex functioning.
Asunto(s)
Receptores de GABA-A/efectos de los fármacos , Receptores de Serotonina/genética , Alprazolam/farmacología , Animales , Ansiolíticos/farmacología , Diazepam/farmacología , Etanol/farmacología , Fiebre/etiología , Fiebre/metabolismo , Flumazenil/farmacología , Antagonistas del GABA/farmacología , Hipnóticos y Sedantes/farmacología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Noqueados , Pentilenotetrazol/farmacología , Fenobarbital/farmacología , Receptores de Serotonina 5-HT1 , Reflejo/efectos de los fármacos , Especificidad de la Especie , Estrés Fisiológico/complicacionesRESUMEN
The behavioral effects of corticotropin-releasing hormone (CRH) appear to depend on the baseline state of arousal of the animal. In this study, this hypothesis was tested using a 4-min maternal separation procedure in 7-day-old male and female mouse pups (outbred CFW strain). Two intensities of stress were used to assess the effects of intracerebroventricularly administered r/hCRH: a mild stress condition where the ambient temperature was close to nest temperature (30 degrees C) and rates of maternal separation-induced ultrasonic vocalizations (USVs) were relatively low (ca. 25/4 min), and a more stressful condition where the temperature was 19 degrees C and the rates of USVs were high (ca. 250/4 min). Differential effects of CRH on vocalization rate and locomotor behavior were observed to be dependent on the level of stress. In the more stressful 19 degrees C condition, r/hCRH dose-dependently reduced the number of USVs without affecting motor behavior, as indexed by grid crossings. In contrast, in the 30 degrees C condition, only the highest dose of r/hCRH reduced calling while r/hCRH activated motor behavior over a wider range of doses. These effects were independent of hypothalamus-pituitary-adrenal (HPA) axis activity, as measured by plasma corticosterone levels. The present study indicates that in mouse pups, the effects of CRH administration depend on baseline levels of arousal and that the behavioral effects of CRH administration can be dissociated under mild and more stressful conditions.
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Ansiedad de Separación/psicología , Hormona Liberadora de Corticotropina/farmacología , Privación Materna , Actividad Motora/efectos de los fármacos , Vocalización Animal/efectos de los fármacos , Animales , Temperatura Corporal/fisiología , Corticosterona/sangre , Hormona Liberadora de Corticotropina/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/fisiología , Inyecciones Intraventriculares , Masculino , RatonesRESUMEN
BACKGROUND: Hypersecretion of corticotropin-releasing hormone (CRH) in the brain has been implicated in stress-related human pathologies. We developed a transgenic mouse line overexpressing CRH (CRH-OE) exclusively in neural tissues to assess the effect of long-term CRH overproduction on regulation of the hypothalamic-pituitary-adrenal (HPA) axis. METHODS: Male transgenic CRH-OE(2122) mice on a C57BL/6J background were used. Littermate wildtype mice served as control animals. Basal plasma corticotropin and corticosterone concentrations were measured, and adrenal gland weight was determined. A dexamethasone suppression test measured the effects of long-term CRH hypersecretion on negative feedback control. Additionally, we measured plasma corticosterone concentrations in reaction to stress. RESULTS: CRH-OE(2122) mice showed elevated basal plasma corticosterone concentrations, hypertrophy of the adrenal gland, and dexamethasone nonsuppression. Basal plasma ACTH concentrations of wildtype and CRH-OE(2122) mice did not differ significantly. In reaction to stress, CRH-OE(2122) mice showed a normal corticosterone response. CONCLUSIONS: The HPA axis abnormalities observed in CRH-OE(2122) mice suggest that long-term hypersecretion of CRH in the brain can be a main cause of HPA axis dysregulation. The alterations in HPA axis regulation are reminiscent of changes reported in major depressive disorder. As such, these CRH -OE(2122) mice may model the neuroendocrine changes observed in major depressive disorder.
Asunto(s)
Hormona Liberadora de Corticotropina/fisiología , Sistema Hipotálamo-Hipofisario/fisiología , Sistema Hipófiso-Suprarrenal/fisiología , Hormona Adrenocorticotrópica/sangre , Animales , Hormona Liberadora de Corticotropina/biosíntesis , Hormona Liberadora de Corticotropina/sangre , Regulación de la Expresión Génica , Genotipo , Ratones , Ratones Transgénicos , Estrés Fisiológico/sangreRESUMEN
BACKGROUND: Corticotropin-releasing hormone (CRH) hyperactivity in transgenic mice overexpressing CRH in the brain (CRH-OE(2122)) appears to be associated with chronic stress-like alterations, including increased CRH content in the hypothalamus, changes in hypothalamus-pituitary-adrenal axis regulation, and increased heart rate and body temperature. In the present study, we investigated if sensory information processing of startling auditory stimuli was affected in CRH-OE(2122) mice. METHODS: CRH-OE(2122) mice (on C57BL/6J background) were subjected to a number of procedures probing sensory information processing mechanisms, including the acoustic startle response, habituation, and prepulse inhibition of startle. RESULTS: CRH-OE(2122) mice displayed reduced acoustic startle reactivity and increased motor activity during startle testing compared to wild-type mice. Furthermore, transgenic mice did not show habituation of the startle response after repeated exposure to the auditory stimulus, or habituation across procedures. CRH-OE(2122) mice exhibited robust impairments of prepulse inhibition in two different paradigms. CONCLUSIONS: The results in CRH-OE(2122) mice indicate that chronic CRH hyperactivity is associated with reductions in startle reactivity, habituation, and prepulse inhibition. The latter two abnormalities are also observed in schizophrenia patients. We conclude that chronic CRH excess may reduce behavioral reactivity to environmental stimuli and impair information processing mechanisms.
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Nivel de Alerta/genética , Hormona Liberadora de Corticotropina/genética , Plasticidad Neuronal/genética , Reflejo de Sobresalto/genética , Estimulación Acústica , Animales , Expresión Génica/fisiología , Habituación Psicofisiológica/genética , Sistema Hipotálamo-Hipofisario/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Inhibición Neural/genética , Sistema Hipófiso-Suprarrenal/fisiologíaRESUMEN
RATIONALE: Recently, a new putative animal model of anxiety, "light-enhanced startle" was introduced. By placing a rat in a brightly lit environment, which is a naturally aversive stimulus to rats, the amplitude of the startle response to a startle-eliciting noise burst is increased. OBJECTIVES: The present study aimed to determine the predictive validity of the light-enhanced startle as a putative model for anxiety. METHODS: The effects of the GABA(A)-benzodiazepine receptor agonist chlordiazepoxide (CDP), the 5-HT1A receptor agonist flesinoxan and the specific 5-HT reuptake inhibitor fluvoxamine on light-enhanced startle were studied. RESULTS: Both CDP and flesinoxan decreased startle potentiation, whereas fluvoxamine was devoid of any effects on potentiation. Effects on baseline startle amplitude were only seen after CDP administration. CONCLUSIONS: The present experiment provides evidence for the predictive validity of the light-enhanced startle as an animal model for anxiety. Due to the use of an unconditioned anxiogenic stimulus, the light-enhanced startle offers several benefits over animal models that depend on conditioning. Drug effects can be ascribed more directly to effects on anxiety, as opposed to memory retrieval and, as shown in this study, non-specific drug effects can easily be detected without the interference of contextual fear.
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Ansiolíticos/farmacología , Ansiedad/tratamiento farmacológico , Ansiedad/etiología , Clordiazepóxido/farmacología , Fluvoxamina/farmacología , Luz , Piperazinas/farmacología , Reflejo de Sobresalto/efectos de los fármacos , Animales , Ansiolíticos/uso terapéutico , Clordiazepóxido/uso terapéutico , Oscuridad , Modelos Animales de Enfermedad , Fluvoxamina/uso terapéutico , Masculino , Piperazinas/uso terapéutico , Ratas , Ratas Wistar , Reflejo de Sobresalto/fisiologíaRESUMEN
Two presynaptic receptors play an important role in the regulation of serotonergic neurotransmission, i.e., the 5-HT(1A) and 5-HT(1B) receptor. The present study focuses on putative adaptive changes in the 5-HT(1A) receptor system in mice that lack 5-HT(1B) receptors (5-HT(1B) KO). 5-HT(1A) receptor sensitivity was assessed in vivo in two models of presynaptic 5-HT(1A) receptor activity: agonist-induced hypothermia and prevention of stress-induced hyperthermia. The effects of 5-HT(1A) receptor activation by flesinoxan (0.1-3.0 mg/kg s.c.) were determined telemetrically on body temperature and heart rate in 5-HT(1B) KO and wild-type (WT) mice. Flesinoxan induced hypothermia dose-dependently without affecting heart rate and prevented stress-induced hyperthermia and tachycardia equipotently in both genotypes. Specificity of these responses was confirmed by blockade with the selective 5-HT(1A) receptor antagonist WAY100635 (1.0 mg/kg s.c.). The importance of continuous sampling in freely moving subjects to improve appropriate characterization of mutants is discussed. 5-HT(1B) KO mice showed no shift in 5-HT(1A) receptor sensitivity compared to WT mice. This study found no indications for adaptive changes in presynaptic 5-HT(1A) receptor function in 5-HT(1B) KO mice as measured telemetrically on body temperature and heart rate responses.