Fluoxetine is a selective serotonin reuptake inhibitor and does not appreciably inhibit norepinephrine and dopamine reuptake. Nevertheless, Eli Lilly researchers found that a single injection of a large dose of fluoxetine given to a rat also resulted in a significant increase of brain concentrations of norepinephrine and dopamine.[78][79][80] This effect may be mediated by 5HT2a and, in particular, 5HT2c receptors, which are inhibited by higher concentrations of fluoxetine. The Eli Lilly scientists also suggested that the effects on dopamine and norepinephrine may contribute to the antidepressant action of fluoxetine.[80]
In the opinion of other researchers, however, the magnitude of this effect is unclear.[73] The dopamine and norepinephrine increase was not observed at a smaller, more clinically relevant dose of fluoxetine.[81] Similarly, in electrophysiological studies only larger and not smaller doses of fluoxetine changed the activity of rat's norepinephrinergic neurons. Some authors, however, argue that these findings may still have clinical relevance for the treatment of severe illness with supratherapeutic doses (60–80 mg) of fluoxetine.[82] Among SSRIs, 'fluoxetine is the least "selective" of all the SSRIs, with a 10-fold difference in binding affinity between its first and second neural targets (i.e., the serotonin and norepinephrine uptake pumps, respectively)'. Anything greater than a 10-fold difference results in insignificant activation of the secondary neuronal targets.[83]