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. ? ? ?
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