RESUMEN
It is unclear whether the poor autonomic flexibility or dysregulation observed in patients with posttraumatic stress disorder (PTSD) represents a pre-trauma vulnerability factor or results from exposure to trauma. We used an animal model of PTSD to assess the association between the behavioral response to predator scent stress (PSS) and the cardiac autonomic modulation in male and female rats. The rats were surgically implanted with radiotelemetry devices to measure their electrocardiograms and locomotor activity (LMA). Following baseline telemetric monitoring, the animals were exposed to PSS or sham-PSS. Continuous telemetric monitoring (24h/day sampling) was performed over the course of 7days. The electrocardiographic recordings were analyzed using the time- and frequency-domain indexes of heart rate variability (HRV). The behavioral response patterns were assessed using the elevated plus maze and acoustic startle response paradigms for the retrospective classification of individuals according to the PTSD-related cut-off behavioral criteria. During resting conditions, the male rats had significantly higher heart rates (HR) and lower HRV parameters than the female rats during both the active and inactive phases of the daily cycle. Immediately after PSS exposure, both the female and male rats demonstrated a robust increase in HR and a marked drop in HRV parameters, with a shift of sympathovagal balance towards sympathetic predominance. In both sexes, autonomic system habituation and recovery were selectively inhibited in the rats whose behavior was extremely disrupted after exposure to PSS. However, in the female rats, exposure to the PSS produced fewer EBR rats, with a more rapid recovery curve than that of the male rats. PSS did not induce changes to the circadian rhythm of the LMA. According to our results, PTSD can be conceptualized as a disorder that is related to failure-of-recovery mechanisms that impede the restitution of physiological homeostasis.
Asunto(s)
Enfermedades del Sistema Nervioso Autónomo/etiología , Caracteres Sexuales , Trastornos por Estrés Postraumático/complicaciones , Estrés Psicológico/fisiopatología , Estimulación Acústica , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Electrocardiografía , Femenino , Frecuencia Cardíaca/fisiología , Masculino , Aprendizaje por Laberinto , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/fisiología , TelemetríaRESUMEN
In mammals, the circadian and stress systems are involved in adaptation to predictable and unpredictable stimuli, respectively. A series of experiments examined the relationship between stress-induced posttraumatic stress (PTSD)-like behavioral response patterns in rats and brain levels of genes related to circadian rhythms. The effects of agomelatine, administered immediately after exposure, on stress-related behavior and on local expression of Per1 and Per2 were assessed. Animals were exposed to predator scent stress. The outcome measures included behavior in an elevated plus-maze (EPM) and acoustic startle response (ASR) 7days after the exposure. Pre-set cut-off behavioral criteria classified exposed animals according to behavioral responses in EPM and ASR paradigms as those with 'extreme behavioral response' (EBR), 'minimal behavioral response (MBR),' or 'partial behavioral response' (PBR). Per1 and Per2 expression in hippocampal subregions, frontal cortex and suprachiasmatic nucleus (SCN) 8days after exposure were evaluated using immunohistochemical and RT-PCR techniques at zeitgeber-times 19 and 13. The effects of agomelatine, on behavioral tests were evaluated on Day 8. Local brain expression of Per1 and Per2 mRNA was subsequently assessed. Data were analyzed in relation to individual behavior patterns. Animals with extreme behavioral response (EBR) displayed a distinct pattern of Per1 and Per2 expression in the SCN, which was the opposite of that observed in the control and MBR animals. In the DG, no variation in Per2 expression was observed in the EBR and PBR animals. Immediate post-exposure treatment with agomelatine significantly reduced percentage of extreme-responders and normalized the expression of Per1 and Per2 as compared to controls. Stress-induced alterations in Per genes in the EBR animals may represent an imbalance between normally precisely orchestrated physiological and behavioral processes and psychopathological processes. These findings indicate that these circadian-related genes play a role in the neurobiological response to predator scent stress and provide supportive evidence that the use of agomelatine immediately after traumatic experience may be protective against the subsequent development of PTSD.
Asunto(s)
Acetamidas/farmacología , Encéfalo/efectos de los fármacos , Ritmo Circadiano/genética , Expresión Génica/efectos de los fármacos , Proteínas Circadianas Period/genética , Estrés Psicológico/genética , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Encéfalo/metabolismo , Proteínas Circadianas Period/metabolismo , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiología , Estrés Psicológico/metabolismoRESUMEN
The therapeutic value of ß-adrenoceptor blockage, using propranolol, in the aftermath of traumatic experience is uncertain. A prospective, controlled animal model of posttraumatic stress disorder (PTSD) was employed to assess the effects of propranolol on long-term behavioral responses to stress. Animals exposed to predator scent stress received a single bolus of propranolol (10 or 15mg/kg) or vehicle 1h post-exposure. Outcomes were assessed using the elevated plus-maze (EPM) and acoustic startle response (ASR) at 30days and freezing response to a trauma reminder (unsoiled litter) on Day 31. Individual animals were classified as having "extreme", "partial" and "minimal" behavioral responses, according to pre-set cut-off criteria for EPM and ASR response patterns. The physiological efficacy of the doses of propranolol was verified by collecting cardiovascular data telemetrically (from exposed or unexposed individuals given propranolol or vehicle). The effect of propranolol on long-term memory was verified using a non-spatial memory task. Both doses of propranolol effectively reduced mean heart rate and impaired the object-recognition task, as expected. No significant effect on prevalence rates of PTSD-like behavioral responses or on trauma reminder response was observed for either dose of propranolol as compared to vehicle. Despite adequate efficacy in terms of heart rate and disruption of memory, single-dose, post-stress ß-blockage with propranolol was ineffective in reducing onset of PTSD-like behavioral disruption and trauma cue responses in the long term. Traumatic stress-related processes appear to be affected differently than the others.