Elsevier

Physiology & Behavior

Volume 87, Issue 5, 30 May 2006, Pages 881-890
Physiology & Behavior

Cortical/hippocampal monoamines, HPA-axis changes and aversive behavior following stress and restress in an animal model of post-traumatic stress disorder

https://doi.org/10.1016/j.physbeh.2006.01.033Get rights and content

Abstract

Post-traumatic stress disorder (PTSD) is characterized by monoaminergic and hypothalamic–pituitary–adrenal (HPA)-axis abnormalities. Understanding monoamine-HPA-axis responses following stress and restress may provide a greater understanding of the neurobiology of PTSD and of its treatment. Hippocampal and frontal cortex serotonin, noradrenaline and dopamine, plasma corticosterone and aversive behavior were studied in rats on day 1 and day 7 post acute stress (AS = sequential restraint stress, swim stress and halothane exposure), and on day 1 and day 7 post restress (RS = swim stress). After AS, there was an early increase in both avoidant behavior and corticosterone (1 h after stress), with subsequent normalisation (day 7), suggesting an adequate adaptive response to the stressor. However, restress (RS) evoked a significant early HPA-axis hyporesponsiveness (1 h after RS) and a later significant increase in avoidant behavior on day 7 post RS. Hippocampal serotonin, noradrenaline and dopamine concentrations were unchanged 1 h post AS, but were significantly raised on day 7 post AS. Restress, however, reduced serotonin and noradrenaline levels 1 h after and on day 7 post RS, respectively, while dopamine was unchanged. In the frontal cortex only dopamine levels were altered, being significantly elevated 1 h after AS, and reduced on day 7 post RS. AS and RS thus differently effect the HPA-axis, evoking regional-specific brain monoamine changes that underlie maladaptive behavior and other post stress-related sequelae.

Introduction

The hypothalamic–pituitary–adrenal (HPA)-axis and the monoaminergic–sympathetic nervous system play an important role in how an animal deals with stress [1]. Where the catecholamines facilitate the availability of energy to vital organs, glucocorticoids released from the adrenals have been proposed to play an important role in containing the neural responses initiated by the stressor [1], [2]. However, the duration and nature of an applied stressor, as well as genetic predisposition, are important determinants whether adaptation to the stress response reverts from being protective to being damaging [3], [4], [5], [6]. Adaptive responses to stress involve short-term activation of the HPA-axis (allostasis), while maladaptive responses result in dysregulation (e.g. over- or under-production) of stress hormones and a failure to terminate activation of the HPA-axis and the genesis of a psychiatric illness (allostatic load; [4], [6]).

Post-traumatic stress disorder (PTSD) is a severely disabling anxiety disorder that may occur following exposure to a severely traumatic event [7]. While the role of glucocorticoids, particularly cortisol, in the psychobiology of PTSD is evident, clinical studies on HPA-axis activity during PTSD have been inconsistent [8], [9], [10], [11]. Evidence for hypocortisolemia in PTSD [11] is particular interesting, such that the exact role of cortisol in trauma and later development of PTSD remains unclear. The HPA response to stress is ultimately terminated by the negative feedback inhibition of cortisol via glucocorticoid receptors in the pituitary, hypothalamus and extra-hypothalamic brain sites [1], [3]. The evidence for a hyper-responsivity of this negative feedback system in PTSD, resulting in hypocortisolemia [12], suggests that the stress response is no longer able to remain in a state of homeostasis. Indeed, low cortisol levels are noted in the presence of high catecholamine levels in patients with PTSD [12]. Some authors have argued from these data that individuals who develop PTSD respond to a traumatic event by failing to release sufficient levels of cortisol for a long-enough period of time to shut down stress-induced sympathetic nervous system responses [13], speculating that there is an exaggerated conditioned autonomic reaction to thoughts related to the trauma, such as increased heart rate, skin conductance, raised blood pressure and anxiety.

The successful management of PTSD with the selective serotonin (5HT) reuptake inhibitors (SRI's; [14]) has increased attention to the role of 5HT in the neurobiology and treatment of PTSD. Actions of these drugs at 5HT1A and 5HT2A receptors in critical limbic regions appear central to their anxiolytic and antidepressant actions [15]. 5HT1A receptors densely populate the hippocampus [16] and play a key role in influencing HPA-axis activity [17], [18], and mood and anxiety. 5HT2 receptors, on the other hand, preferentially populate the cortical areas [19] but also serve to activate the HPA-axis [20] and have pronounced effects on mood and anxiety. Important to note is that stress induces a varied response on 5HT release depending on the brain region studied and the type and duration of the applied stressor (for example see [21], [22], [23], [24]).

Other monoamine systems also play a role, particularly the noradrenergic [25] and dopaminergic [26] systems. The NA'ergic system acts as an arousal and alerting system and facilitates transmission in many brain regions, interacting with corticotropic releasing factor (CRF; [27]), and playing an important role in the amygdala where it is involved in conditioned fear responses and facilitating the retrieval of fear memory [28], [29]. Acute and chronically stressed rats show significant elevations in noradrenergic activity in the prefrontal cortex and hippocampus [30], [31], [32], and it is not surprising that altered noradrenergic transmission has been implicated in a number of anxiety disorders [33]. Mesolimbic dopaminergic pathways similarly play a profound role in states of fear and anxiety, with overactivation of dopamine transmission exacerbating the fear response, and inhibition thereof reducing conditioned fear [26]. While acute stress increases dopamine levels in the prefrontal cortex [32], [34] and hippocampus [35], [36], [37], its relationship to clinical anxiety disorders is more complex and poorly understood, as is its role in PTSD. Nevertheless, evidence suggests a causal role for frontal cortex DA dysfunction in the intrusive thoughts and diminished extinction of trauma-related memory that are characteristic features of PTSD [26], [38], [39], [40], [41].

Animal models of PTSD have utilised intense stressors, aversive challenges, and situational reminders of a traumatic event, in an attempt to model long-term effects on behavioral, autonomic, and hormonal responses seen in humans with PTSD [42]. Of critical importance is that activation of stress-regulatory circuits is highly dependent on the type of stressor applied [43]. Moreover, multiple exposures to trauma are now increasingly being recognised as crucial in predicting the onset and severity of the disorder [44]. In the present study, we have used a time dependent sensitisation (TDS) model that employs the sequential exposure to a somatosensory stressor (restraint), an inescapable or psychological stressor (forced swimming), followed by a complex stress-stimuli evoked by exposure to halothane. Together these comprise the acute stressor, followed by re-exposure to swim stress 7 days later. TDS is a useful behavioral paradigm that closely correlates with key behavioral and neuroendocrine changes seen in PTSD [45], but particularly hypocortisolemia [46], exaggerated startle response [47] and cognitive deficits [48]. Moreover, in agreement with the clinical efficacy of serotonergic drugs in the treatment of PTSD [14], TDS also induces distinct serotonergic receptor abnormalities in the hippocampus and FC [48] while associated bio-behavioral changes are blocked by fluoxetine [49]. The rationale of the model is that repeated exposure to stress plays an important role in the development of an abnormal response to a later stressor [42], and also in the development of PTSD [50]. Since NA, 5HT and DA seem to occupy separate roles in the stress response, the aim of this particular study was to investigate changes in hippocampal and frontal cortex (FC) monoamines in rats following AS and a reminder 7 days later (RS) and to relate these changes to plasma corticosterone and aversive behavior on the elevated plus maze (EPM). Differential monoaminergic and HPA-axis activity after acute stress and after re-experience may provide new insight into the neurobiology and treatment of PTSD.

Section snippets

Animals

Male Sprague–Dawley rats (170–200 g), provided by the Laboratory Animal Center of the Potchefstroom campus, were used in all aspects of the study. Ethical approval for the study was granted by the Ethical committee of the North-West University (no. 03D07). The rats were housed in cages (5 rats per cage) with a width of 28 cm, a length of 44.5 cm and a height of 12.5 cm. The conditions in the animal center were controlled at 21 ± 0.5 °C and 50 ± 5% relative humidity. Full spectrum cold white light,

Effect of halothane alone on rat brain monoamines

In order to accurately interpret the effects of the AS procedure, and the effect of halothane alone on brain monoamines, halothane was administered to control, unstressed animals and compared to control. Halothane alone did not significantly alter hippocampal NA, DA and 5HT levels compared to control (p > 0.05; t-test; Table 1). However, the drug induced a significant increase in frontal cortex NA (p = 0.03; t-test; Table 1), and a significant decrease in frontal cortex DA (p = 0.003; t-test; Table 1

Discussion

An inability to appropriately initiate or regulate the stress response has been proposed to be a critical factor in the pathology of PTSD [1], [2], [3], [4]. In this study, an acute severe stressor (AS) produced a pronounced state of aversive behavior, as determined on the EPM (Fig. 1a), which waned over the ensuing 7 days. An accompanying increase in plasma corticosterone immediately after AS, and its normalization on day 7 post AS, suggests that the animal is displaying a normal adaptive

Acknowledgements

The South African Medical Research Council (BHH, DJS and LB) and the National Research Foundation (BHH, grant number 2053203) for financial support; Cor Bester, Antoinette Fick and Dr. Douw van der Nest for the welfare of the animals; Francois Viljoen for assistance with the HPLC analyses; Prof. Tiaan Brink for the statistical analysis.

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