Acute citalopram has different effects on regional 5-HT synthesis in FSL, FRL, and SDP rats: An autoradiographic evaluation

Abstract

In this study, we measured the effect of an acute treatment of citalopram on 5-HT synthesis in a genetic rat model of depression, the Flinders Sensitive Line (FSL) rats, their counterparts, the Flinders Resistant Line (FRL) rats, and outbred Sprague-Dawley (SPD) rats, using the α-[ 14 C]methyl-Ltryptophan (α-MTrp) autoradiographic method. A comparison of 5-HT synthesis in the FSL rats treated with citalopram (FSL-CTP) and those treated with saline (FSL-SAL) indicate that citalopram reduces global 5-HT synthesis in the FSL rats, as well as in all the brain areas investigated. The reduced synthesis was also observed in the dorsal raphe nucleus (DR) and the median raphe nucleus (MR). The comparison of the synthesis between the citalopram treated SPD rats (SPD-CTP) and the saline treated SPD rats (SPD-SAL) revealed a global increase of 5-HT synthesis in the SPD-CTP group, as well as an increase in some terminal areas, but a reduction in the DR and the MR. In contrast to the reduction throughout the brain in the FSL rats, the FRL rats treated with citalopram (FRL-CTP), when compared to the saline group (FRL-SAL), showed a global increase of 5-HT synthesis, as well as in most of the terminal areas and in the DR and the MR. The reduction of 5-HT synthesis throughout the brain in the FSL rats is likely a result of reported supersensitivity of the 5-HT 1A receptors. Comparing changes in the SPD, FRL, and FSL rats treated with citalopram to their respective controls (saline treated rats), the FSL rats treated acutely with citalopram were the only rats that exhibited lower 5-HT synthesis rates in all of the limbic areas, the basal ganglia, and the neocortices. This may be related to the pathophysiological basis of depressive characteristics in FSL rats. The citalopram treatment produced unexpected results in the FRL rats: 5-HT synthesis was elevated not only in most of the terminal areas, but also in the cell body areas, the DR and MR. The increase of 5-HT synthesis throughout the brain in the FRL rats is likely a result of the reported subsensitivity of the 5-HT 1A receptors, and possibly other sites through which 5-HT synthesis could be controlled (e.g., 5-HT 1B ). In addition differences in intracellular signaling could be at least in part responsible for these differences. 4Correspondence to;

Acute treatment with fluvoxamine elevates rat brain serotonin synthesis in some terminal regions: An autoradiographic study

“…However, this presumption is unlikely given that no difference in plasma free tryptophan levels was observed between the fluvoxamine and control group of rats in the present study. This is also in line with no effect of fluoxetine [28], citalopram [4,31] and paroxetine [32] treatments on plasma tryptophan levels in rats.…”

“…Further, as was the case with these other drugs, fluvoxamine decreased the 5-HT synthesis rate in the nuclei raphe, although its effect was less expressed and related mostly to 5-HT synthesis in the raphe magnus nucleus. The increase in the 5-HT synthesis rate in the areas of nerve terminals that was found after fluvoxamine was also observed in the above mentioned studies [4,28,31,33], but with slight differences in specific regions between the studies. The only exception was the study with paroxetine [32], in which decreased or unchanged (cortices) 5-HT synthesis rates were found in the axon terminals.…”

“…We have published numerous papers that included the set of representative autoradiograms [4,21,22,[28][29][30]. Given this, and the fact that there is little information of value provided by this set, we did not include them in the current paper.…”

“…Previous studies have shown that the acute application of citalopram [4,31], fluoxetine [28], paroxetine [32] and fenfluramine [33] affects 5-HT synthesis rates similar to fluvoxamine in a different regionally specific manner. Further, as was the case with these other drugs, fluvoxamine decreased the 5-HT synthesis rate in the nuclei raphe, although its effect was less expressed and related mostly to 5-HT synthesis in the raphe magnus nucleus.…”

“…Several neurochemical and behavioural studies [3][4][5] have found alterations in serotonergic neurotransmission after treatment with various classes of antidepressant drugs, including selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRI), such as fluvoxamine [6].…”