TY - JOUR
T1 - Role of brain norepinephrine in the behavioral response to stress
AU - Morilak, David A.
AU - Barrera, Gabe
AU - Echevarria, David J.
AU - Garcia, April S.
AU - Hernandez, Angelica
AU - Ma, Shuaike
AU - Petre, Corina O.
N1 - Funding Information:
Original research conducted in the authors laboratory was supported by research grants from the National Institute of Mental Health (MH60118 and MH53851), and from the Veterans Administration and Department of Defense. All experiments and procedures described were reviewed and approved by the Institutional Animal Care and Use Committee of the University of Texas Health Science Center at San Antonio, and were consistent with NIH guidelines for the care and use of laboratory animals. The authors would like to acknowledge the contributions made to original research described in this paper by Dr. Marco Cecchi, Dr. Habibeh Khoshbouei, Dr. Marie-Christine Pardon, and Ms. Lauren Phillips. Some of the material in this review has been modified from material presented in a previous review chapter by Morilak, D.A., “Norepinephrine and Stress”, in Norepinephrine: Neurobiology and Therapeutics , (G. Ordway, M. Schwartz and A. Frazer, eds.), Cambridge Press, in press .
PY - 2005/12
Y1 - 2005/12
N2 - 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.
AB - 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.
KW - Antidepressant
KW - Anxiety
KW - Behavior
KW - Microdialysis
KW - Norepinephrine
KW - Stress
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U2 - 10.1016/j.pnpbp.2005.08.007
DO - 10.1016/j.pnpbp.2005.08.007
M3 - Review article
C2 - 16226365
AN - SCOPUS:27944444457
SN - 0278-5846
VL - 29
SP - 1214
EP - 1224
JO - Progress in Neuro-Psychopharmacology and Biological Psychiatry
JF - Progress in Neuro-Psychopharmacology and Biological Psychiatry
IS - 8
ER -