Understanding the molecular pharmacology of the serotonergic system: using fluoxetine as a model

Abstract

Keywords AbstractObjectives Serotonin is a monoamine neurotransmitter that is widely distributed in the body and plays an important role in a variety of psychological and other body functions such as mood, sexual desire and function, appetite, sleep, memory and learning, temperature regulation and social behaviour. This review will assess the use of fluoxetine, one of the most commonly used selective serotonin reuptake inhibitors, as a model for understanding the molecular pharmacology of the serotoninergic system. Key findings Seven serotonin receptor families have been discovered to date. All serotonin receptors, except 5-HT3, are G-protein coupled, seven transmembrane receptors that activate an intracellular second messenger cascade. The 5-HT3 receptor is a ligand-gated ion channel. Furthermore, 5-HT1A receptors are known as autoreceptors since their stimulation inhibits the release serotonin in nerve terminals. A transporter protein found in the plasma membrane of serotonergic neurones is responsible for the reuptake of this neurotransmitter. Selective serotonin reuptake inhibitors, such as fluoxetine, act primarily at the serotonin transporter protein and have limited, if any, reaction with other neurotransmitter systems. Selective serotonin reuptake inhibitors appear to bind with the serotonin transporter with different rates of occupancy, duration and potency. Summary The following review focuses on the interaction of serotonin with this membrane transporter in the body and assesses the use of fluoxetine as a reference drug in the understanding of this interaction.

Study on anti-inflammatory and immunomodulatory effects of fluoxetine in rat models of inflammation

“…It blocks serotonin transporter protein by high-affinity mechanism and increases the concentration of this mediator in the central nervous system (CNS) and peripheral tissues. 3 Experimental data showed that along with its main pharmacological effect -antidepressivefluoxetine has ant-inflammatory activity. 4 Studies on the anti-inflammatory activity of antidepressants are of interest in several areas.…”

Fluoxetine Blocks Nav1.5 Channels via a Mechanism Similar to That of Class 1 Antiarrhythmics

“…Since its discovery in 1974 (Wong et al, 1974), the beneficial psychotropic effects of fluoxetine have led to its being used to treat disorders other than depression, including obsessive compulsive disorders and bulimia nervosa (Wong et al, 1995). The multiple side effects of fluoxetine (Sghendo and Mifsud, 2012) have raised questions about its supposed selective serotonin-mediated effect. Fluoxetine inhibits the serotonin transporter (SERT) in the low nanomolar range (Torres et al, 2003), but its therapeutic effect appears only at much higher plasma and brain concentrations (Muscettola et al, 1978;Bolo et al, 2000).…”

Perinatal serotonergic activity: A decisive factor in the control of food intake

“…One of the degradation pathways of serotonin is performed by the enzymes monoamine oxidase A and B, breaking down serotonin into 5-hydroxyindoleacetic acid [21]. A second mechanism of serotonin degradation regards its reuptake by its transporter, located in the pre-synaptic membrane [22]. SERT is the main agent responsible for the regulation of 5-HT levels in the synaptic gap.…”

“…The function of this cell membrane protein is to reuptake 5-HT that has not been broken down by monoamine oxidase in the synaptic gap and transfer it to the inside of the pre-synaptic neurons [22]. Active removal increases the speed in which the levels of neurotransmitter in the synaptic gap decrease, restricting the effects of 5-HT to smaller areas, and recycles some of the neurotransmitter relased in the synapse for later use [22]. By changing its conformation, SERT moves one or more serotonin molecules per cycle, unlike transmembrane channels, which remain open or closed.…”

“…This mechanism may be responsible for the quick development of serotonergic neurons and for the transitory presence of 5-HT in some neurons during development [15]. The synthesis of 5-HT from tryptophan increases in response to the frequency of electrical stimulation of the serotonergic cell body [16,22]. Short-term requirements for higher 5-HT synthesis may occur by changing the kinetic properties of TPH without the need to increase TPH level [28].…”