Discriminative stimulus properties of the selective norepinephrine reuptake inhibitor, reboxetine, in rats

Rationale: Although drug discrimination procedures have proven difficult to apply to antidepressant agents, we recently characterized discriminative stimulus properties of the selective serotonin (5-HT) reuptake inhibitor, citalopram, in rats. However, discriminative stimulus properties of selective norepinephrine (NE) reuptake inhibitors remain to be evaluated. Objective: We determined the potential discriminative stimulus properties of the highly selective NE reuptake inhibitor and antidepressant, reboxetine. Methods: Employing a two-lever discrimination procedure, rats were trained to discriminate reboxetine (2.5 mg/kg, IP) from saline. In parallel, the influence of reboxetine (2.5 mg/kg) upon dialysate levels of monoamines in frontal cortex and dorsal hippocampus of freely moving rats was determined. Results: After 54 +/- 10 training sessions, reboxetine elicited robust stimulus recognition, fully generalizing to itself with an ED50 of 1.2 mg/kg. Two further NE reuptake inhibitors, desipramine (5.3) and maprotiline (1.8), as well as the 5-HT/NE reuptake inhibitor, venlafaxine (1.0), likewise generalized. In contrast, the 5-HT reuptake inhibitors, paroxetine, citalopram and sertraline, and the DA reuptake inhibitors, GBR12935 and bupropion, did not show significant generalization. Reboxetine markedly increased dialysate levels of NE, but not 5-HT, in frontal cortex and hippocampus. Dopamine (DA) levels were also (though less markedly) enhanced in frontal cortex. Conclusion: In parallel with an elevation in extracellular levels of NE, the selective NE reuptake inhibitor, reboxetine, elicits a specific discriminative stimulus in rats.