Long‐term treatment with fluoxetine induces desensitization of 5‐HT₄ receptor‐dependent signalling and functionality in rat brain

Abstract

The mode of action of antidepressant drugs may be related to mechanisms of monoamines receptor adaptation, including serotonin 5-HT 4 receptor subtypes. Here we investigated the effects of repeated treatment with the selective serotonin reuptake inhibitor fluoxetine for 21 days (5 and 10 mg/kg, p.o., once daily) on the sensitivity of 5-HT 4 receptors by using receptor autoradiography, adenylate cyclase assays and extracellular recording techniques in rat brain. Fluoxetine treatment decreased the density of 5-HT 4 receptor binding in the CA1 field of hippocampus as well as in several areas of the striatum over the doses of 5-10 mg/kg. In a similar way, we found a significant lower response to zacopride-stimulated adenylate cyclase activity in the fluoxetine 10 mg/kg/day treated group. Furthermore, post-synaptic 5-HT 4 receptor activity in hippocampus-measured as the excitatory action of zacopride in the pyramidal cells of CA1 evoked by Schaffer collateral stimulation was attenuated in rats treated with both doses of fluoxetine. Taken together, these results support the concept that a net decrease in the signalization pathway of 5-HT 4 receptors occurs after chronic selective serotonin reuptake inhibitor treatment: this effect may underlie the therapeutic efficacy of these drugs.

Chronic Fluoxetine Selectively Upregulates Dopamine D1-Like Receptors in the Hippocampus

“…Chronic fluoxetine caused an overall decrease in the [ 3 H]GR113808 binding (Figure 4a), which is consistent with previous results (Licht et al, 2009;Vidal et al, 2009). The decrease was evident in the striatum, amygdala, and substantia nigra, but did not reach the statistical significance in the hippocampus (Figure 4b).…”

Neuroadaptations of the 5-HT System Induced by Antidepressant Treatments: Old and New Strategies

“…This is in agreement with earlier studies showing a desensitization and a downregulation of SERT following repeated administrations of paroxetine or sertraline [68,69]. Other neuroadaptive changes were reported after chronic fluoxetine such as a desensitization of 5-HT7 receptors [53] and a downregulation of their binding sites in the hypothalamus [73], as well as a downregulation of 5-HT4 binding sites in the CA1 field of the hippocampus [74].…”

Fluoxetine: a case history of its discovery and preclinical development

“…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].…”