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

Abstract

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 M) inhibited [3 H]5-HT uptake; however, the maximal degree of inhibition achieved was 70%. Addition of nomifensine (1-10 M) was required for complete inhibition of Despite their lower affinity for serotonin (5-hydroxytryptamine; 5-HT), there is experimental evidence to suggest that catecholaminergic neurons may take up and store 5-HT. Indeed, 5-HT-immunoreactive fibers in the pars intermedia of the rat pituitary gland can be eliminated by treatment with 6-hydroxydopamine, a neurotoxin selective for catecholamine neurons (Saland et al., 1986). Interestingly, Thind and coworkers (1987) observed the presence of 5-HT staining in tyrosine hydroxylase-immunoreactive fibers in the suprachiasmatic nuclei and ventromedial hypothalamus 24 h after infundibular stalk section. These authors proposed that catecholaminergic terminals might take up 5-HT coming from cut 5-HT terminals. In a study by Feuerstein and coworkers (1986), prolonged incubations of caudate nucleus slices with [ 3 H]5-HT led to labeling of catecholaminergic terminals, which was prevented by the NE/DA uptake inhibitor nomifensine but not by the selective 5-HT reuptake inhibitor 6-nitroquipazine. The above observations suggest that storage of 5-HT may occur in catecholamine-containing neurons. Based on the above described findings, we proposed that in brain areas where there is a coexistence of catecholaminergic and serotonergic terminals, 5-HT could accumulate in catecholaminergic neurons if the 5-HT neuronal transporter (neuronal uptake pump) is inhibited with a selective 5-HT transporter inhibitor. To test this hypothesis, we employed the olfactory tubercle of the rabbit because of its high density of 5-HT, DA, and NE terminals (Dahlstrom and Fuxe, 1964;Conzolazione and Cuello, 1982;Fallon and Moore, 1987). In addition, the olfactory tubercle is a limbic region of easy access and could be a relevant site of action for antidepressant drugs (Rosin et al., 1995). Citalopram was used as the selective serotonin reuptake inhibitor (SSRI) (Sitte et al., 2000). The experimental rationale was based on the assumption that incubation with low concentrations of [ 3 H]5-HT results in selective labeling of 5-HT terminals, whereas incubation of [ 3 H]5-HT in the presence of citalopram would favor labeling of catecholaminergic neurons. In addition, based on the higher affinity of the 5-HT terminals for 5-HT, we proposed that nonradioactive 5-HT should be more potent than NE and DA in displacing [3 H]5-HT, when the [ 3 H]5-HT is stored in serotonergic terminals. Such specificity should be lost if the 5-HT would be stored in catecholaminergic terminals. Our findings suggest that catecholaminergic terminals take up 5-HT when the 5-HT uptake pump is inhibited with the SSRI, citalopram.ABBREVIATIONS:5-HT, serotonin; NE, norepinephrine; DA, dopam...

Neurochemical and behavioral consequences of striatal injection of 5,7-dihydroxytryptamine

“…These results show that 5,7-DHT can also damage DA, at least when injected in doses of 25-50 g into the ventral striatum, and this effect can be abolished when inhibiting DA transporters by nomifensine. On the other hand, nomifensine treatment diminished 5HT damage in a dose-dependent way, possible since nomifensine might also partially inhibit 5HT transporters (Suarez-Roca and Cubeddu, 2002). To limit this unwanted 5HT effect, we decided to use the lower dose of nomifensine in the final experiment.…”

The promiscuity of the dopamine transporter: Implications for the kinetic analysis of [3H]serotonin uptake in rat hippocampal and striatal synaptosomes

“…First, the increased values for K m and V max in striatal versus hippocampal synaptosomes appear to be due to significant 5-HT uptake via DAT. This is not surprising considering that striatal neurons establish synaptic contact with both DAT-and SERTexpressing terminals (Graybiel and Ragsdale, 1983) and that 5-HT can be transported as a substrate for DAT and modulate DAT activity (Stamford et al, 1990, Jacocks and Cox, 1992, Jackson and Wightman, 1995, De Deurwaerdere et al, 1996, Suarez-Roca and Cubeddu, 2002, Zhou et al, 2002, Riddle et al, 2003, Callaghan et al, 2005. Second, the concentration of fluoxetine (10 μM) used for defining nonspecific [ 3 H]5-HT uptake in striatal synaptosomes appears to have inhibited DAT.…”

“…In another study, Zhou and colleagues (2005) showed that striatal dopaminergic terminals will take up 5-HT and subsequently release both 5-HT and DA when SERT is inhibited by a serotonin specific reuptake inhibitor (SSRI) and extracelluar levels of 5-HT are elevated. In addition, 5-HT was found to be taken up, stored, and subsequently released by catecholaminergic neurons in rabbit olfactory tubercle under conditions in which serotonin transporter (SERT) activity was inhibited by the SSRI, citalopram (Suarez-Roca and Cubeddu, 2002). Riddle et al (2003) extended these findings by showing that ceramide, an agent known to alter the phosphorylation state of transporter proteins, increases 5-HT uptake and reduces DA uptake through DAT.…”

Dopaminergic neurones: much more than dopamine?

“…However, such an ‘intimate’ interaction as the one described by Zhou et al . had not been directly demonstrated before, despite some preliminary suggestive evidence ( Stamford et al ., 1990 ; Suarez‐Roca & Cubeddu, 2002 ).…”