Changes in monoaminergic neurotransmission contribute to time-dependent modifications in behavior, affect and cognition that comprise both the antidepressant and anxiolytic effects of chronic antidepressant drug treatment, including selective norepinephrine (NE) reuptake inhibitors such as desipramine (DMI). Elevation of tonic levels of noradrenergic activity has been implicated in arousal, vigilance, and attention, which could improve inhibitory symptoms of depression. However, anxiety is also a prominent component of depression, and phasic, acute stress-evoked activation of noradrenergic neurotransmission enhances anxiety-like behavioral responses to stress. Therefore, it is unclear how enhancing NE transmission could contribute to anxiolytic as well as antidepressant effects. Nonetheless, selective NE reuptake inhibitors are effective in resolving anxiety-related symptoms as well as inhibitory symptoms of depression. Thus, in this project, we hypothesize that chronic NE reuptake blockade differentially regulates tonic- and phasically-activated noradrenergic transmission to account for this dual effect. To test this, we propose a series of experiments using microdialysis, together with a series of behavioral pharmacological studies, to examine time-dependent neurochemical changes in noradrenergic neurotransmission, and corresponding changes in behavioral measures of attentional set-shifting capability and acute anxiety-like behavioral reactivity on the elevated plus-maze and defensive burying tests, after chronic treatment of rats with DMI. We predict that tonically elevating noradrenergic activity in the medial prefrontal cortex will enhance arousal and attention, but that a concurrent attenuation of phasic, stress-activated NE neurotransmission in limbic regions such as the bed nucleus of the stria terminalis and lateral septum via autoreceptor-mediated inhibition, will reduce acute anxiety-like behavioral stress reactivity. Key observations made following DMI treatment will also be verified using other selective NE reuptake inhibitors, reboxetine and atomoxetine, which lack the potential non- selective post-synaptic antagonist activity of DMI. Relevant to the NIMH mission, a better understanding of how these regulatory processes contribute to both antidepressant and anxiolytic efficacy of AD drugs may offer novel insights for future development of more effective, more specific or more rapid treatment, or even ultimately to the prevention of serious mental health problems such as depression and anxiety disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Winsky, Lois M
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University of Texas Health Science Center San Antonio
Schools of Medicine
San Antonio
United States
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Girotti, Milena; Adler, Samantha M; Bulin, Sarah E et al. (2017) Prefrontal cortex executive processes affected by stress in health and disease. Prog Neuropsychopharmacol Biol Psychiatry :
Fucich, Elizabeth A; Paredes, Denisse; Morilak, David A (2016) Therapeutic Effects of Extinction Learning as a Model of Exposure Therapy in Rats. Neuropsychopharmacology 41:3092-3102
Radley, Jason; Morilak, David; Viau, Victor et al. (2015) Chronic stress and brain plasticity: Mechanisms underlying adaptive and maladaptive changes and implications for stress-related CNS disorders. Neurosci Biobehav Rev 58:79-91
Jett, Julianne D; Boley, Angela M; Girotti, Milena et al. (2015) Antidepressant-like cognitive and behavioral effects of acute ketamine administration associated with plasticity in the ventral hippocampus to medial prefrontal cortex pathway. Psychopharmacology (Berl) 232:3123-33
Donegan, Jennifer J; Patton, Michael S; Chavera, Teresa S et al. (2015) Interleukin-6 attenuates serotonin 2a receptor signaling by activating the JAK-STAT pathway. Mol Pharmacol 87:492-500
Donegan, Jennifer J; Girotti, Milena; Weinberg, Marc S et al. (2014) A novel role for brain interleukin-6: facilitation of cognitive flexibility in rat orbitofrontal cortex. J Neurosci 34:953-62
Furr, Ashley; Lapiz-Bluhm, M Danet; Morilak, David A (2012) 5-HT2A receptors in the orbitofrontal cortex facilitate reversal learning and contribute to the beneficial cognitive effects of chronic citalopram treatment in rats. Int J Neuropsychopharmacol 15:1295-305
Morilak, David A (2012) Modulating the modulators: interaction of brain norepinephrine and cannabinoids in stress. Exp Neurol 238:145-8
Girotti, Milena; Donegan, Jennifer J; Morilak, David A (2011) Chronic intermittent cold stress sensitizes neuro-immune reactivity in the rat brain. Psychoneuroendocrinology 36:1164-74
Campeau, Serge; Liberzon, Israel; Morilak, David et al. (2011) Stress modulation of cognitive and affective processes. Stress 14:503-19

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