Article

Role of brain norepinephrine in the behavioral 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: 4.03). 01/2006; 29(8):1214-24. DOI: 10.1016/j.pnpbp.2005.08.007
Source: PubMed

ABSTRACT 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.
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    • "There are three subtypes of α 1 -adrenergic receptors, namely α 1A , α 1B and α 1D that function as stimulatory receptors in response to the physiological agonist NA (Docherty, 2010). The NAergic system and central α 1 -adrenoceptors are involved in the regulation of a large variety of physiologic and pathologic emotional processes, including positively and aversively motivated behaviors, fear and anxiety (Morilak et al., 2005). It is therefore conceivable that changes induced by early life adverse events may be reflected by the alteration of the central NAergic system and expression of various subclasses of adrenergic receptors in adult life. "
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    • "However, stress-induced alterations in sleep duration and fragmentation are well known in humans and rodents (Mezick et al., 2009; Pawlyk et al., 2008). WKY rats are widely known to exhibit high susceptibility to stressor and inability to adapt to stress (Morilak et al., 2005; Pare, 1989; Pare and Redei, 1993; Redei et al., 1994). Thus, it is possible that that WKY rats do not adapt to repeated sleep restriction due to elevated norepinephrine tone (in addition to corticosterone) throughout the period of CSR especially when the sleep deprivation method is fairly stressful. "
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