Vol. 302, Issue 1, 174-179, July 2002

The Selective Serotonin Reuptake Inhibitor Citalopram Induces the Storage of Serotonin in Catecholaminergic Terminals

Heberto Suarez-Roca and Luigi X. Cubeddu

Pharmacology Section, Instituto de Investigaciones Clinicas, School of Medicine, University of Zulia, Maracaibo, Venezuela (H.S.-R.); Clinical Pharmacology and Neuropharmacology Units, Department of Pharmacology, School of Pharmacy, Central University of Venezuela, Caracas, Venezuela (L.X.C.); and Nova Southeastern University, Health Professions Division, Fort Lauderdale, Florida (L.X.C.)

We investigated whether selective inhibition of serotonin (5-hydroxytryptamine; 5-HT) transporter with citalopram leads to accumulation of 5-HT in catecholaminergic neurons. In the rabbit olfactory tubercle, citalopram (1-10 µM) inhibited [³H]5-HT uptake; however, the maximal degree of inhibition achieved was 70%. Addition of nomifensine (1-10 µM) was required for complete inhibition of [³H]5-HT uptake. In slices labeled with 0.1 µM [³H]5-HT, cold 5-HT (0.03-1 µM) induced a large increase in the efflux (release) of stored [³H]5-HT, an effect blocked by coperfusion with 1 µM citalopram. Similar concentrations (0.03-1 µM) of norepinephrine (NE) or dopamine (DA) failed to release [³H]5-HT. When labeling with 0.1 µM [³H]5-HT was carried out in the presence of citalopram, 1) low concentrations of 5-HT failed to release [³H]5-HT; 2) DA and NE were more potent and effective in releasing [³H]5-HT than in control slices; 3) coperfusion of NE, DA, or 5-HT with citalopram enhanced the release of [³H]5-HT induced by the catecholamines but not by 5-HT; and 4) coperfusion of NE or DA with nomifensine antagonized NE- and DA-evoked [³H]5-HT release, with a greater effect on NE than on DA. These results suggest that in the rabbit olfactory tubercle, where there is coexistence of 5-HT, NE, and DA neurons, inhibition of the 5-HT transporter led to accumulation of 5-HT in catecholaminergic terminals. Thus, during treatment with selective serotonin uptake inhibitors (SSRIs), 5-HT may be stored in catecholaminergic neurons acting as a false neurotransmitter and/or affecting the disposition of DA and/or NE. Transmitter relocation may be involved in the antidepressant action of SSRIs.