The role of norepinephrine in the behavioural response to stress

Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, 78229-3900, USA.
Progress in Neuro-Psychopharmacology and Biological Psychiatry (Impact Factor: 3.69). 01/2006; 29(8):1214-24. DOI: 10.1016/j.pnpbp.2005.08.007
Source: PubMed


The brain noradrenergic system is activated by acute stress. The post-synaptic effects of norepinephrine (NE), exerted at a cellular or neural circuit level, have been described as modulatory in nature, as NE facilitates responses evoked in target cells by both excitatory and inhibitory afferent input. Over the past few years, we have undertaken a series of studies to understand how these cellular modulatory effects of NE, elicited by acute stress, might translate into modulation of the behavioral-affective components of the whole-animal response to stress. Using microdialysis, we have demonstrated that acute immobilization stress activates NE release in a number of stress-related limbic forebrain target regions, such as the central and medial amygdala, lateral bed nucleus of the stria terminalis, medial prefrontal cortex, and lateral septum. Using microinjections of adrenergic antagonist drugs directly into these regions, we have shown that this stress-induced release of NE facilitates a number of anxiety-like behavioral responses that are mediated in these regions, including stress-induced reduction of open-arm exploration on the elevated plus-maze, stress-induced reduction of social interaction behavior, and activation of defensive burying behavior by contact with an electrified probe. Dysregulation of the brain noradrenergic system may be a factor in determining vulnerability to stress-related pathology, or in the interaction of genetic vulnerability and environmental sensitization. Compared to outbred Sprague-Dawley rats, we have shown that the modulatory effect of NE is deficient in Wistar-Kyoto rats, which also exhibit attenuated behavioral reactivity to acute stress, as well as increased vulnerability to stress-induced gastric ulcers and exaggerated activation of the hypothalamic-pituitary-adrenal (HPA) stress axis. Further, repeated exposure to mild intermittent cold stress resulted in a much greater sensitization of both the brain noradrenergic system and the HPA axis in Wistar-Kyoto rats compared to Sprague-Dawley rats. The recruitment of a robust noradrenergic facilitatory influence following repeated cold exposure in this previously deficient strain resulted in an aberrant HPA response, which may be illustrative of the kinds of neurobiological changes that may contribute to the development of stress-related neuropsychiatric disorders such as depression, post-traumatic stress disorder, or other anxiety disorders in predisposed or susceptible individuals. On the other side of the same issue, regulatory alterations in noradrenergic neurotransmission, or in the stress-modulatory functions of NE, may be important in the behavioral effects of chronic antidepressant drug treatment. We present recent preliminary results addressing the effects of chronic treatment with the selective NE reuptake inhibitor, desipramine, on acute behavioral reactivity to stress. A better understanding of the role of NE in adaptive responses to acute stress, the pathological consequences of prolonged, repeated or severe stress, and the mechanisms of action of drugs used to treat stress-related diseases, may contribute to the future development of more effective strategies for the treatment or even prevention of such disorders.

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    • "Besides dysregulation of the hypothalamic pituitary adrenal (HPA) axis, considerable clinical evidence suggests central noradrenergic system involvement in PTSD neuropathology (Southwick et al. 1999; O'Donnell et al. 2004; Strawn and Geracioti 2008; Pervanidou and Chrousos 2010). The locus coeruleus (LC), origin of the majority of noradrenergic neurons, is the primary source of norepinephrine (NE) in the forebrain thus, mediating a variety of brain functions and behaviors such as arousal, memory acquisition, attention, vigilance, and responses to stress (Aston-Jones et al. 1996; Morilak et al. 2005; Valentino and Van Bockstaele 2008; "
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    ABSTRACT: Dysregulation of the central noradrenergic system is core feature of PTSD. Here, we examined molecular changes in locus coeruleus (LC) triggered by single prolonged stress (SPS) PTSD model at a time when behavioral symptoms are manifested, and the effect of early intervention with intranasal NPY. Immediately following SPS stressors, male SD rats were administered intranasal NPY (SPS/NPY) or vehicle (SPS/V). Seven days later, TH protein, but not mRNA, was elevated in LC only of SPS/V group. Although 90% of TH positive cells expressed GR, its levels were unaltered. Compared to unstressed controls, LC of SPS/V, but not SPS/NPY, expressed less Y2 receptor mRNA with more CRHR1 mRNA in subset of animals, and elevated CRH in central nucleus of amygdala.Following testing for anxiety on EPM, there were significantly increased TH, DBH and NPY mRNAs in LC of SPS-treated, but not previously unstressed animals. Their levels highly correlated with each other but not with behavioral features on EPM. Thus, SPS triggers long-term noradrenergic activation and higher sensitivity to mild stressor, perhaps mediated by the upregulation of influence of amygdalar CRH input and downregulation of Y2R presynaptic inhibition in LC. Results also demonstrate therapeutic potential of early intervention with intranasal NPY for traumatic stress-elicited noradrenergic impairments.This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 09/2015; DOI:10.1111/jnc.13347 · 4.28 Impact Factor
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    • "As indicated by the HPLC analysis (Section 3.2), stress-provoked responses in tissue NA content in the GR DBHCre female (compared with wt animals) but not male mice may be an important factor that contributes to their phenotype. Considering that the tissues were collected 30 min after restraint stress, the decreased levels of NA in the GR DBHCre mice after acute stress may suggest higher NA output under the stress conditions, which is associated with the quick metabolic process of this neurotransmitter in female mutants (Morilak et al., 2005). Surprisingly , acute restraint stress was also associated with a gender specific effect of diminished 5-HIAA (the main metabolite of 5-HT) content in the PFC, which suggests down-regulation of this monoamine system in female GR DBHCre mutants. "
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    ABSTRACT: Recently, we have demonstrated that conditional inactivation of glucocorticoid receptors (GRs) in the noradrenergic system, may evoke depressive-like behavior in female but not male mutant mice (GR(DBHCre) mice). The aim of the current study was to dissect how selective ablation of glucocorticoid signaling in the noradrenergic system influences the previously reported depressive-like phenotype and whether it might be linked to neurotrophic alterations or secondary changes in the serotonergic system. We demonstrated that selective depletion of GRs enhances brain derived neurotrophic factor (BDNF) expression in female but not male GR(DBHCre) mice on both the mRNA and protein levels. The possible impact of the mutation on brain noradrenergic and serotonergic systems was addressed by investigating the tissue neurotransmitter levels under basal conditions and after acute restraint stress. The findings indicated a stress-provoked differential response in tissue noradrenaline content in the GR(DBHCre) female but not male mutant mice. An analogous gender-specific effect was identified in the diminished content of 5-hydroxyindoleacetic acid, the main metabolite of serotonin, in the prefrontal cortex, which suggests down-regulation of this monoamine system in female GR(DBHCre) mice. The lack of GR also resulted in an up-regulation of alpha2-adrenergic receptor (α2-AR) density in the female but not male mutants in the locus coeruleus. We have also confirmed the utility of the investigated model in pharmacological studies, which demonstrates that the depressive-like phenotype of GR(DBHCre) female mice can be reversed by antidepressant treatment with desipramine or fluoxetine, with the latter drug evoking more pronounced effects. Overall, our study validates the use of female GR(DBHCre) mice as an interesting and novel genetic tool for the investigation of the cross-connected mechanisms of depression that is not only based on behavioral phenotypes.
    Pharmacology Biochemistry and Behavior 08/2015; 137. DOI:10.1016/j.pbb.2015.08.001 · 2.78 Impact Factor
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    • "In addition to the HPA axis, exposure to stress also activates the sympatho-adrenomedullary system resulting in enhanced norepinephrine (NE) levels in multiple brain regions, including the hippocampus (reviewed in Pacak et al., 1995; Morilak et al., 2005). Stress-evoked NE release, along with CRH, is known to influence central nervous system stress responses (reviewed in Morilak et al., 2005; Lloyd and Nemeroff, 2011). Together adrenergic neurotransmission, hypothalamic CRH and circulating GCs also act as the primary mediators of the peripheral Figure 1: Maladaptive consequences of chronic adult stressors on hippocampal structural plasticity, physiological responses and hippocampus-dependent behaviors. "
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    ABSTRACT: Exposure to stressors elicits a spectrum of responses that span from potentially adaptive to maladaptive consequences at the structural, cellular and physiological level. These responses are particularly pronounced in the hippocampus where they also appear to influence hippocampal-dependent cognitive function and emotionality. The factors that influence the nature of stress-evoked consequences include the chronicity, severity, predictability and controllability of the stressors. In addition to adult-onset stress, early life stress also elicits a wide range of structural and functional responses, which often exhibit life-long persistence. However, the outcome of early stress exposure is often contingent on the environment experienced in adulthood, and could either aid in stress coping or could serve to enhance susceptibility to the negative consequences of adult stress. This review comprehensively examines the consequences of adult and early life stressors on the hippocampus, with a focus on their effects on neurogenesis, neuronal survival, structural and synaptic plasticity and hippocampal-dependent behaviors. Further, we discuss potential factors that may tip stress-evoked consequences from being potentially adaptive to largely maladaptive.
    Reviews in the neurosciences 04/2015; DOI:10.1515/revneuro-2014-0083 · 3.33 Impact Factor
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