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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    • "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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    • "Acute noradrenergic response to stress—measured by tyrosine hydroxylase mRNA levels, noradrenaline (NA) release, or c-fos stimulation—is also attenuated in WKY rats compared to Sprague-Dawley rats (Pardon et al., 2002). By contrast, chronic stress results in a greater sensitization of the hypothalamic-pituitary-adrenal axis and central noradrenergic system in WKY as compared to Sprague-Dawley rats (Morilak et al., 2005). A recent electrophysiological study shows that neuronal basal firing rate of the locus coeruleus (LC) nucleus is augmented and the sensitivity of α 2 -adrenoceptors reduced in WKY as compared to Wis rats (Bruzos-Cidon et al., 2014). "
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    ABSTRACT: Background: The noradrenergic nucleus locus coeruleus (LC) has functional relevance in several psychopathologies such as stress, anxiety and depression. In addition to glutamatergic and GABAergic synaptic inputs, the activation of somatodendritic α2-adrenoceptors is the main responsible for LC activity regulation. The Wistar Kyoto (WKY) rat exhibits depressive- and anxiety-like behaviours and hyperresponse to stressors. Thus, the goal of the present study was to investigate in vitro the sensitivity of α2-adrenoceptors, as well as the glutamatergic and GABAergic synaptic activity on LC neurons of the WKY strain. Methods: For that purpose, using patch-clamp whole-cell recordings were useddone in LC slices. Results: The α2-adrenoceptors of LC neurons from WKY rats were less sensitive to the effect induced by the agonist UK 14,304 as compared to that recorded in the Wistar (Wis) control strain. In addition, the GABAergic input to LC neurons of WKY rats was significantly modified compared to that in Wis rats, since the amplitude of sIPSC was reduced and the half-width increased. On the contrary, no significant alterations were detected regarding glutamatergic input to LC neurons between rat strains. Conclusions: These results point out that in WKY rats the inhibitory control exerted by α2-adrenoceptors and GABAergic input onto LC neurons is dysregulated. Overall, this study supports in this animal model the hypothesis that claims an unbalance between the glutamatergic-GABAergic systems as a key factor in the pathophysiology of depression. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 01/2015; 18(7). DOI:10.1093/ijnp/pyu122 · 4.01 Impact Factor
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    • "Interestingly, anatomical evidence has shown that there is also a monosynaptic projection from VTA to LC (Beckstead et al., 1979), and that stimulation of VTA increases the concentration of NE metabolites in PFC (Deutch et al., 1986). Furthermore, previous studies indicated that both NE and DA provide essential modulatory influences on prefrontal functions (Mingote et al., 2004; Arnsten and Li, 2005; Aston-Jones and Cohen, 2005b; Morilak et al., 2005; Rossetti and Carboni, 2005; Drouin et al., 2006). "
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    ABSTRACT: Cognitive functions associated with prefrontal cortex (PFC), such as working memory and attention, are strongly influenced by catecholamine [dopamine (DA) and norepinephrine (NE)] release. Midbrain dopaminergic neurons in the ventral tegmental area and noradrenergic neurons in the locus coeruleus are major sources of DA and NE to the PFC. It is traditionally believed that DA and NE neurons are homogeneous with highly divergent axons innervating multiple terminal fields and once released, DA and NE individually or complementarily modulate the prefrontal functions and other brain regions. However, recent studies indicate that both DA and NE neurons in the mammalian brain are heterogeneous with a great degree of diversity, including their developmental lineages, molecular phenotypes, projection targets, afferent inputs, synaptic connectivity, physiological properties, and behavioral functions. These diverse characteristics could potentially endow DA and NE neurons with distinct roles in executive function, and alterations in their responses to genetic and epigenetic risk factors during development may contribute to distinct phenotypic and functional changes in disease states. In this review of recent literature, we discuss how these advances in DA and NE neurons change our thinking of catecholamine influences in cognitive functions in the brain, especially functions related to PFC. We review how the projection-target specific populations of neurons in these two systems execute their functions in both normal and abnormal conditions. Additionally, we explore what open questions remain and suggest where future research needs to move in order to provide a novel insight into the cause of neuropsychiatric disorders related to DA and NE systems.
    Frontiers in Neural Circuits 05/2014; 8. DOI:10.3389/fncir.2014.00053 · 3.60 Impact Factor
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