The selective serotonin reuptake inhibitor citalopram induces the storage of serotonin in catecholaminergic terminals

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.