Effects of chronic treatment with fluoxetine and citalopram on 5-HT uptake, 5-HT1B autoreceptors, 5-HT3 and 5-HT4 receptors in rats

Abstract

The effect in rats of chronic treatment with two specific 5-HT reuptake inhibitors (SSRI) with antidepressant properties, citalopram (10 mg/kg, i.p. twice a day for 14 days, one day washout) and fluoxetine (15 mg/kg, p.o. twice a day for 21 days, 7 days washout), was evaluated on some mechanisms involved in central 5-HT neurotransmission. No adaptive modifications of brain 5-HT uptake (sites) were found by measuring functional [3H]5-HT uptake and [3H]citalopram binding in cortical and hippocampal synaptosomes, and by [3H]citalopram binding autoradiography in the raphe nuclei (5-HT cell bodies) and the ventral tegmental area (5-HT axonal pathway). Chronic treatments had no effect on presynaptic 5-HT1B autoreceptors, functionally evaluated by measuring 5-HT1B-mediated inhibition of depolarization-induced [3H]5-HT release from cortical and hippocampal synaptosomes. Chronic citalopram or fluoxetine did not significantly affect the binding of [3H]BRL-43694 to 5-HT3 receptors in the rat brain cortex. Citalopram had no effect on [125I]SB-207710 binding to 5-HT4 receptors, measured by autoradiography in the substantia nigra. Negative results, such as those reported in the present study, could be due to a number of variables including the animal species, the treatment schedule or the brain areas considered, thus explaining the differences from some previous reports of significant effects of SSRI. However, our negative data are in agreement with many other published studies, suggesting that adaptive modifications of brain 5-HT transporters, terminal 5-HT1B receptors, 5-HT3 and 5-HT4 receptors may not be a general effect induced by all SSRI.

A Nonlinear Relationship between Cerebral Serotonin Transporter and 5-HT2AReceptor Binding: AnIn VivoMolecular Imaging Study in Humans

“…This interpretation is in accordance with our observation of a high interregional correlation of 5-HT 2A receptor binding, which is suggestive of a common regulator, presumably the raphe serotonergic output. Given that the 5-HT 2A receptor binding is accepted as a surrogate marker of cerebral 5-HT levels and that SERT binding adjusts to 5-HT levels in a manner suggested from some, although not all, experimental studies (Graham et al, 1987;Kovachich et al, 1992;Cheetham et al, 1993;Pineyro et al, 1994;Rattray et al, 1996;Gobbi et al, 1997;Benmansour et al, 1999;Horschitz et al, 2001;Benmansour et al, 2002;Evrard et al, 2002;Gould et al, 2003Gould et al, , 2006Rothman et al, 2003), our observation of an inverted U-shaped relation between 5-HT 2A receptor and SERT binding may be the result of inter-individual differences in cerebral baseline 5-HT levels.…”

“…In vitro autoradiography and homogenate binding experiments in rats suggest that a decrease in SERT binding levels occur after pharmacologically induced chronic extracellular 5-HT depletion in two (Rattray et al, 1996;Rothman et al, 2003) of three studies (no change seen in the study by Dewar et al, 1992). Chronically elevated extracellular 5-HT levels have usually been achieved by chronic treatment with the specific selective serotonin reuptake inhibitor (SSRI) compounds sertraline, citalopram, and paroxetine, and, in 10 ( Kovachich et al, 1992;Pineyro et al, 1994;Benmansour et al, 1999;Horschitz et al, 2001;Benmansour et al, 2002;Gould et al, 2003Gould et al, , 2006Rossi et al, 2008) of 15 experimental settings (no change reported in the studies by Graham et al, 1987;Kovachich et al, 1992;Cheetham et al, 1993;Gobbi et al, 1997;Gould et al, 2006), decreased SERT levels have been found. It can be argued, however, that chronic blockade of the SERT may lead to regulation of its expression and that the primary cause for the SERT downregulation is unrelated to 5-HT levels.…”

Fluoxetine: a case history of its discovery and preclinical development

“…Furthermore, there is evidence that the persistent increase in extracellular 5-HT induced by chronic fluoxetine might be explained by the desensitisation of terminal 5-HT 1B autoreceptors, whose activation exerts a feedback inhibition of 5-HT release, as demonstrated by electrophysiology and microdialysis assays [42,43]. Accordingly, the support for fluoxetine-induced 5-HT 1B subsensitivity came from the decrease in receptor expression observed [44], although other reports did not confirm this effect [36,45]. Other explanations of the mechanism of action of fluoxetine after long-term treatment have also been proposed.…”

“…For example, the role of other 5-HT receptors has been evoked, given that chronic fluoxetine treatment also downregulates the density of 5-HT 4 receptors and produces a functional desensitisation involving the adenylate cyclase system [46]. By contrast, long-term treatment does not provoke robust alterations in other 5-HT receptors, such as 5-HT 2 or 5-HT 3 [45,47,48]. In addition, there is some controversy regarding the role of 5-HT transporters in the adaptive changes following chronic fluoxetine administration [36,38,44].…”

Delayed pharmacological effects of antidepressants

“…20 However, the literature on the effects of long-term antidepressants on the serotonin transporter (SERT) or norepinephrine transporter (NET) are inconsistent. [21][22][23][24][25][26][27] We decided to re-examine this issue, and speculated that two factors needed to be addressed in our studies. One was how the drugs are administered.…”