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.
    Reviews in the neurosciences 04/2015; DOI:10.1515/revneuro-2014-0083 · 3.31 Impact Factor
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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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    ABSTRACT: Exposure to adversity during early life is a risk factor for the development of different mood and psychiatric disorders, including depressive-like behaviors. Here, neonatal mice were temporarily but repeatedly (day 1 to day 13) separated from mothers and placed in a testing environment containing a layer of odorless clean bedding (CB). We assessed in adult animals the impact of this early experience on binding sites and mRNA expression of α1-adrenergic receptor subtypes, heat shock proteins (HSPs) and proapoptotic and antiapoptotic members of the Bcl-2 family proteins in different brain regions involved in processing of olfactory information and rewarding stimuli. We found that repeated exposure to CB experience produced anhedonic-like behavior in terms of reduced saccharin intake and α1-adrenoceptors downregulation in piriform and somatosensory cortices, hippocampus, amygdala and discrete thalamic nuclei. We also found a selective decrease of α1B-adrenoceptor binding sites in the cingulate cortex and hippocampus and an increase of hippocampal α1A and α1B receptor, but not of α1D-adrenoceptor, mRNA levels. Moreover, while a significant decrease of antiapoptotic heat shock proteins Hsp72 and Hsp90 was identified in prefrontal cortex, a parallel increase of antiapoptotic members of Bcl-2 family proteins was found at hippocampal level. Together, these data provide evidence that the early exposure to CB experience produced enduring downregulation of α1-adrenoceptors in the prefrontal-limbic forebrain/limbic midbrain network, which plays a key role in processing of olfactory information and reaction to rewarding stimuli. Finally, these data show that CB experience can "prime" the hippocampal circuitry and promotes the expression of antiapoptotic factors that can confer potential neuroprotection to subsequent adversity.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 10/2013; 48. DOI:10.1016/j.pnpbp.2013.10.004 · 4.03 Impact Factor
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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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    ABSTRACT: Sleep responses to chronic sleep restriction may be very different from those observed after acute total sleep deprivation. Specifically, when sleep restriction is repeated for several consecutive days, animals express attenuated compensatory increases in sleep time and intensity during daily sleep opportunities. The neurobiological mechanisms underlying these adaptive, or more specifically, allostatic, changes in sleep homeostasis are unknown. Several lines of evidence indicate that norepinephrine may play a key role in modulating arousal states and NREM EEG delta power, which is widely recognized as a marker for sleep intensity. Therefore, we investigated time course changes in brain adrenergic receptor mRNA levels in response to chronic sleep restriction using a rat model. Here, we observed that significantly altered mRNA levels of the α1- adrenergic receptor in the basal forebrain as well as α2- and β1- adrenergic receptor in the anterior cingulate cortex only on the first sleep restriction day. On the other hand, the frontal cortex α1-, α2-, and β1- adrenergic receptor mRNA levels were reduced throughout the period of sleep restriction. Combined with our earlier findings on EEG that sleep time and intensity significantly increased only on the first sleep restriction days, these results suggest that alterations in the brain norepinephrine system in the basal forebrain and cingulate cortex may mediate allostatic changes in sleep time and intensity observed during chronic sleep restriction.
    Brain research 08/2013; 1531. DOI:10.1016/j.brainres.2013.07.048 · 2.83 Impact Factor
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