Cortical/hippocampal monoamines, HPA-axis changes and aversive behavior following stress and restress in an animal model of post-traumatic stress disorder
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.
References (68)
- et al.
Stress and the brain
Neurobiol Aging
(2003) Protective and damaging effects of stress mediators: the good and bad sides of the response to stress
J Clin Endocrinol Metab
(2002)- et al.
Neurobiology of posttraumatic stress disorder
Curr Opin Neurobiol
(2000) - et al.
Regional differences in the effects of forced swimming on extracellular levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid
Brain Res
(1995) - et al.
The effects of different stressors on extracellular 5-hydroxytryptamine and 5-hydroxyindoleacetic acid
Brain Res
(1997) Central noradrenergic neurones and stress
Pharmacol Ther
(1995)- et al.
Mesolimbic dopaminergic pathways in fear conditioning
Prog Neurobiol
(2004) - et al.
Posttraumatic stress disorder: a state-of-the-science review
J Psychiatr Res
(2006) - et al.
Individual differences in behavioural reactivity: correlation with stress-induced nor-epinephrine efflux in the hippocampus of Sprague–Dawley rats
Brain Res Bull
(1999) - et al.
Increased dopamine and norepinephrine release in medial pre-frontal cortex induced by acute and chronic stress: effects of diazepam
Neurosci
(1995)
The noradrenergic system in pathological anxiety: a focus on panic with relevance to generalized anxiety and phobias
Biol Psychiatry
Differential effects of nicotine against stress-induced changes in dopaminergic system in rat striatum and hippocampus
Eur J Pharmacol
Effects of immobilisation stress on hippocampal monoamine release: modification by mivazerol, a new alpha-2-adrenoceptor agonist
Neuropharmacology
Modulation of the stress response by coffee: an in vivo microdialysis study of hippocampal serotonin and dopamine levels in rat
Neurosci Lett
The role of mesoprefrontal dopamine neurons in the acquisition and expression of conditioned fear in the rat
Neuroscience
The principal features and mechanisms of dopamine modulation in the prefrontal cortex
Prog Neurobiol
Neurocircuitry of stress: central control of the hypothalamo–pituitary–adrenocortical axis
Trends Neurosci
Criteria for rationally evaluating animal models of posttraumatic stress disorder
Biol Psychiatry
Stress–restress: effects on ACTH and fast feedback
Psychoneuroendocrinology
Endocrine, cognitive and hippocampal/cortical 5HT1A/2A receptor changes evoked by a time-dependent sensitisation (TDS) stress model in rats
Brain Res
Pre- and post-disaster negative life events in relation to the incidence and severity of post-traumatic stress disorder
Psychiatry Res
An assessment of the cerebroprotective potential of volatile anaesthetics using two independent methods in an in vitro model of cerebral ischaemia
Brain Res
Fear and the brain: where are we and where are we going?
Biol Psychiatry
Stress increases noradrenaline release in the rat frontal cortex: prevention by diazepam
Eur J Pharmacol
Urinary dopamine and turn bias in traumatised women with and without PTSD symptoms
Behav Brain Res
High trait anxiety in healthy subjects is associated with low neuroendocrine activity during psychological stress
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
Activity-dependent beta-adrenergic modulation of low-frequency stimulation induced LTP in the hippocampal CA1 region
Neuron
Low platelet-poor plasma concentrations of serotonin in patients with combat-related posttraumatic stress disorder
Biol Psychiatry
Stress doses of hydrocortisone, traumatic memories, and symptoms of posttraumatic stress disorder in patients after cardiac surgery: a randomized study
Biol Psychiatry
Physiological functions of glucocorticoids in stress and their relation to pharmacological actions
Endocr Rev
Hormones, brain and stress
Endocr Regul
Stress and the brain: from adaptation to disease
Nat Rev Neurosci
Protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders
Ann N Y Acad Sci
Diagnostic and statistical manual of mental disorders (DSM-IV)
Cited by (107)
Supplementation of taurine improves ionic homeostasis and mitochondrial function in the rats exhibiting post-traumatic stress disorder-like symptoms
2021, European Journal of Pharmacology