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Abstract

Norepinephrine (NE) in the medial prefrontal cortex (mPFC) modulates behavioral flexibility. States requiring flexibility correlate with higher activity of NE neurons of the locus coeruleus (LC) and elevated mPFC NE release. NE reuptake transporter (NET) inhibitors are used as medications for attention disorders; however, little is known about the mechanisms mediating their efficacy. Most animal studies have tested the behavioral effects of a single injection of a NE drug. However, chronic administration is more relevant for clinical application. Also, injection handling itself may introduce a confounding stress-associated NE release. We administered Atomoxetine (ATM), a NET inhibitor, over 28 days via an intra-peritoneal (i.p.) implanted osmotic pump. After 11 ? 13 days of drug exposure, we measured set-shifting in an operant task that required a shift from visual cue-guided responding to egocentric space-guided responding. ATM (0.1, 0.3, 1.0 mg/kg, N = 8-9 rats per dose) had no effect on set-shifting compared to vehicle. Other studies reported that repeated i.p. injection of a NET inhibitor (Desipramine) or a single ATM injection (0.1 ? 0.9 mg/kg) enhanced shifting between sensory modalities (odor/touch). The inconsistency may be due to the use of a spatial rule. Salient stimuli elicit phasic LC activation that increases the signal-to-noise ratio of sensory neuron activity, while the role of NE in spatial context has not been described. LC and mPFC activity was recorded in saline- and ATM-exposed rats under urethane anesthesia. The effects of ATM on laminar-specific mPFC unit activity and cortical state (LFP) and LC unit activity will be presented.