Loss of serotonin uptake sites and immunoreactivity in rat cortex after dexfenfluramine occur without parallel glial cell reactions

The frontal cortices of rats which received either D,L- or D-fenfluramine (DFEN) for 4 days were examined 18 h to 2 weeks following treatment for changes in synaptosomal uptake of serotonin (5HT), paroxetine binding, 5HT-immunoreactivity (5HT-IR), and both astrocytic (GFAP) and microglial markers. Additional rats received intracerebroventricular injections of the neurotoxin 5,7-dihydroxytryptamine (DHT). Consistent with previous reports, D,L- and DFEN produced dose-dependent losses of both 5HT uptake and paroxetine binding, and loss of 5HT-IR which coincided with an abnormal or 'swollen' appearance of immunoreactive axon processes. Recovery of these serotonergic indices was greatest following the lowest doses of DFEN, but was absent after 5,7-DHT treatment. No evidence for an increase in GFAP synthesis or microglial activation was observed in frontal cortices of rats treated with either DFEN or 5,7-DHT. We conclude that the presence of swollen 5HT-IR axons in the cortices of both the 5,7-DHT and DFEN groups is insufficient to trigger the glial responses often associated with neuronal degeneration. Thus, it remains to be determined if swollen 5HT-IR axons are a prelude to neurodegeneration, or whether they represent reversible changes in axonal immunochemistry associated with decreases in 5HT levels. The implications of the data for the clinical safety of DFEN are briefly discussed.