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Levosulpiride: from gut troubles jumping into the neuronal network of anxiety and depression

What is levosulpiride?

Levosulpiride is a drug belonging to the class of substituted benzamides and acts primarily as a selective antagonist of dopamine D2 receptors. It is used in various psychiatric and gastrointestinal disorders, including depression, anxiety, gastrointestinal motility disorders, and dyspeptic symptoms. Due to its selectivity for dopamine D2 receptors and its peripheral and central action, levosulpiride offers benefits for several clinical conditions, but it also has potential side effects due to dopaminergic modulation. Levosulpiride acts primarily as a selective antagonist of dopamine D2 receptors, but its effects extend beyond dopamine regulation to other neurotransmitter systems.

Molecular mechanisms of action

Effects on central D2 receptors: Levosulpiride inhibits dopamine D2 receptors found primarily in the mesolimbic area and nigrostriatal system of the brain. The reduction of dopaminergic activity in the limbic and mesolimbic areas is useful in the treatment of psychiatric disorders such as depression and anxiety, improving mood and reducing depressive symptoms. Effects on peripheral D2 receptors: At the gastrointestinal level, levosulpiride blocks D2 receptors present in the chemoreceptor area, which contributes to the antiemetic effect and improves gastric motility. This mechanism is useful in the treatment of dyspepsia and other gastrointestinal motor disorders.

Effects on gut motility

Levosulpiride has a prokinetic action that improves the motility of the gastrointestinal tract. By blocking D2 receptors, levosulpiride facilitates the release of acetylcholine in enteric neurons, improving intestinal motility and accelerating gastric emptying. This action is useful in patients with symptoms of functional dyspepsia, gastroparesis and symptoms of gastroesophageal reflux. Blocking D2 receptors in the chemoreceptive trigger zone at the central level allows levosulpiride to have an antiemetic effect. Levosulpiride is used to control nausea and vomiting due to its ability to block dopaminergic transmission in the chemoreceptor zone of the brain, which is responsible for inducing the vomiting reflex. Everyone will be familiar with the drug Plasil for injection and almost everyone will have performed it at least once after nausea and/or vomiting from indigestion.

Effects of levosulpiride on the brain

Levosulpiride has significant effects on the central nervous system, influencing mood, behavior, and pain perception. Levosulpiride’s action on mesolimbic D2 receptors and modulation of dopaminergic transmission lead to improvements in symptoms of anxiety and depression. Inhibition of D2 receptors in the mesolimbic pathways improves depressive symptoms by promoting mood stabilization and improved affect. Levosulpiride may also reduce symptoms of anxiety by improving dopamine regulation in areas of the brain involved in the stress response. Levosulpiride has been studied for its role in modulating pain perception, especially in functional disorders. By blocking D2 receptors in areas involved in pain perception, levosulpiride reduces somatic pain associated with functional gastrointestinal conditions.

Dopamine modulation appears to have beneficial effects on patients with irritable bowel syndrome and other functional pain syndromes, such as chronic back pain. Dopamine blockade may adversely affect short-term memory and learning ability, as dopamine is important for information consolidation. Since dopamine also modulates motivation and attention circuits, D2 receptor antagonism may lead to reduced motivation and mild attention deficit in some subjects. One of the most well-known side effects of levosulpiride is to increase prolactin release from neurons. Blockade of D2 receptors in the hypothalamus prevents dopaminergic inhibition of prolactin, causing increased plasma prolactin levels.

This can lead to galactorrhea (milk secretion), gynecomastia (enlarged breast tissue in men), amenorrhea (absence of menstrual periods), and sexual dysfunction. Increased prolactin can interfere with ovulation and spermatogenesis, compromising fertility in both women and men. There is evidence that prolactin is, among the endocrine signals, a major mediator of seasonal adaptations and seasonal depressive attacks are well known to clinicians. And prolactin is among the endocrine factors that may affect the immune response a well. Prolactin work with receptors analogous to cytokines like IL-6, IL-2 and IFN-gamma, activating the JAK/STAT signaling pathway and regulating the immune response.

A direct correlation between depression and immune function is already demonstrated fro some time now; therefore, the antidepressive effect of levosulpiride may be exerted with a twofer: a direct action on neuronal circuits and an indirect effect mediated by immune regulation. Therefore, this drug may be employed in seasonal affective disorders, where serotonin network is involved. Since levosulpiride is brain-penetrating and may work as a moderate 5-HT3 and 5-HT4 serotonin receptor agonist, this rationale is justified.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Maqsood S et al. Life Sci. 2022; 311(Pt B):121198.

Thakkar KB et al. J Clin Diagn Res. 2013; 7(12):2759.

Leelahanaj T et al. Drug Devel Res. 2005; 64(1), 55-67.

Altamura AC et al. J Psychopharmacol. 2000; 14(1):10.

Mucci A et al. Pharmacol Res. 1995; 31(2):95-101.

Lucchelli A et al. Brit J Pharmacol. 1995; 114(5):1017.

Karol MD et al J Clin Pharmacol. 1992; 32(5), 463-468.

Bouras C et al. Acta Psych Scandin. 1982; 66(5):473.

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Dott. Gianfrancesco Cormaci
Dott. Gianfrancesco Cormaci
Laurea in Medicina e Chirurgia nel 1998; specialista in Biochimica Clinica dal 2002; dottorato in Neurobiologia nel 2006; Ex-ricercatore, ha trascorso 5 anni negli USA (2004-2008) alle dipendenze dell' NIH/NIDA e poi della Johns Hopkins University. Guardia medica presso la casa di Cura Sant'Agata a Catania. Medico penitenziario presso CC.SR. Cavadonna (SR) Si occupa di Medicina Preventiva personalizzata e intolleranze alimentari. Detentore di un brevetto per la fabbricazione di sfarinati gluten-free a partire da regolare farina di grano. Responsabile della sezione R&D della CoFood s.r.l. per la ricerca e sviluppo di nuovi prodotti alimentari, inclusi quelli a fini medici speciali.

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