Antidepressant Drugs Inhibit a Gial 5‐Hydroxytryptamine Transporter in Rat Brain

Abstract

We assessed the role of glial cells in the uptake of serotonin (5‐hydroxytryptamine, 5‐HT). Primary cultures of rat and mouse cortical astrocytes took up and deaminated 5‐HT. The antidepressants citalopram, clomipramine, fluoxetine, fluvoxamine, paroxetine and sertraline inhibited this process. The presence of the mRNAs for the 5‐HT transporter and monoamine oxidase‐A (MOA‐A) was established in cultured astrocytes and in adult rat brain areas with (midbrain and brainstem) and without (frontal cortex) serotonergic cell bodies after reverse transcription‐polymerase chain reaction and hybridization with probes complementary to the cloned neuronal 5‐HT transporter and MAO‐A. To examine in vivo the role of astrocytes in the elimination of 5‐HT from the extracellular brain space, 5‐HT was perfused through dialysis probes implanted in the frontal cortex of conscious rats and its concentration was measured at the probe outlet. Tissue 5‐HT recovery was dose‐dependently inhibited by the concurrent perfusion of citalopram, fluoxetine and paroxetine, showing that it essentially measured uptake through the high‐affinity 5‐HT transporter. Rats lesioned with 5,7‐dihydroxytryptamine (5,7‐DHT; 88% reduction of tissue 5‐HT) displayed tissue 5‐HT recovery slightly higher than sham‐operated rats (55 ± 2 vs. 46 ± 3%, P < 0.001), a finding perhaps attributable to the astrogliosis induced by 5,7‐DHT denervation. Rats lesioned with 6‐hydroxydopamine showed tissue 5‐HT uptake similar to controls, suggesting negligible reuptake of 5‐HT by catecholaminergic terminals. These results are consistent with the presence of a glial component of 5‐HT uptake in the rodent brain, sensitive to antidepressants, which takes place through a 5‐HT transporter very similar or identical to that present in neurons.

The Pro-inflammatory Cytokine TNF-α Regulates the Activity and Expression of the Serotonin Transporter (SERT) in Astrocytes

“…For one of our model systems, namely for primary astrocytes, evidence for functional SERT expression already exists, and we confirmed here results from earlier studies [30,31,33]. Although, the murine SERT promoter was found to be active in C6 glioma cells [42], to our knowledge, SERTspecific uptake had not previously been shown for our second model.…”

“…SERT-specific 5-HT uptake has been detected in primary astrocytes and various glial cells lines [10,29,30], but to our knowledge has not been reported for C6 glioma cells. Thus, we utilized saturation kinetics and various monoamine transporter inhibitors to characterize the high-affinity 5-HT uptake components in these cells.…”

“…However, in recent years, several reports have been published providing compelling evidence for the expression of functionally active SERT in glial cells lines as well as in primary astrocytes [10,[29][30][31]. High-affinity uptake of 5-HT by astrocytes is sensitive to inhibition by antidepressants such as imipramine and SSRIs, with a high degree of correlation noted between the Ki values for inhibition of 5-HT uptake by antidepressants in astrocytes and neurons, thus suggesting that the pharmacologically indistinguishable, highaffinity 5-HT uptake is mediated by SERT in both, glial and neuronal cells [30,32,33]. Furthermore, in recent years glial-derived SERT has been successfully visualized in rat brain tissue [34,35].…”

Hippocampal astrocytes are necessary for antidepressant treatment of learned helplessness rats

“…Future study will be needed to elucidate the mechanism of glutamine in the effects of antidepressants. Second, the impairment of astrocytes may increase extracellular serotonin levels like antidepressant drugs because antidepressant drugs inhibit a glial serotonin transporter in the rat brain, increasing extracellular serotonin levels (Bel et al, 1997). It is likely that increases in extracellular serotonin levels remind us of selective serotonin reuptake inhibitor (SSRI) type of antidepressants.…”

Expression of Monoamine Transporters, Nitric Oxide Synthase 3, and Neurotrophin Genes in Antidepressant-Stimulated Astrocytes

“…However, it has to be said that there are presumably several subtypes of astroglial cells differing in specific protein expression, localization, and function which could explain these discrepancies (Halassa et al, 2007). In contrast, it has been shown that astrocytes in culture can take up serotonin and this can be blocked by SSRIs like fluoxetine (Bal et al, 1997; Inazu et al, 2001). It has therefore been speculated that astrocytes participate in the mode of action of this class of antidepressant drugs.…”