Simultaneous analyses of the neurochemical and behavioral effects of the norepinephrine reuptake inhibitor reboxetine in a rat model of antidepressant action

Rationale: The forced swimming test (FST) is a rodent behavioral assay widely used to predict clinical efficacy of putative antidepressants. Few studies have examined the effects of the FST on neurotransmitter levels and how antidepressant drug treatment may alter neurotransmitter levels and behavior simultaneously during the performance of a stressful task. Objectives: The present study examined the role of norepinephrine in mediating active behaviors in the FST after treatment with reboxetine, a selective norepinephrine reuptake inhibitor. Methods: High-pressure liquid chromatography was used to analyze microdialysis samples collected from awake, freely moving rats before, during and after exposure to the FST. Reboxetine (10 mg/kg) was given three times over a 24-h period prior to the test swim. Behavioral responses, including immobility, swimming and climbing, were counted during the 5-min test on day 1 and day 2. Results: The first exposure to swim stress elicited a 65% increase in extracellular norepinephrine (NE). A second exposure on day 2 elicited a 52% increase of NE and a behavioral profile characterized by increased immobility and a reduction of active behaviors. A subchronic course (three injections over 24 h) of treatment with reboxetine between the two swim exposures resulted in antidepressant-like activity, i.e., decreased immobility and increased climbing behavior on day 2. A significantly greater increase in extracellular NE (112%) was observed in the group of animals that received reboxetine injections. Conclusions: Treatment with reboxetine in a schedule commonly used in the FST resulted in a potentiated noradrenergic response to the swim challenge concomitant with behavioral alterations consistent with antidepressant-like activity.