P. de Deurwaerdère et G. Di Giovanni inProg Neurobiol
Serotonergic modulation of the activity of mesencephalic dopaminergic systems: Therapeutic implications.
De Deurwaerdère P, Di Giovanni G. Serotonergic modulation of the activity of mesencephalic dopaminergic systems: Therapeutic implications. Review. Prog Neurobiol. 2016 Mar 22. pii: S0301-0082(15)30096-4. 2016 review.
Philippe de Deurwaerdère : Professeur de Neurosciences et Neuropharmacologie / Team leader : Neurochemistry, deep brain stimulation and Parkinson’s disease / Université de Bordeaux / Institut des Maladies Neurodégénératives / UMR CNRS 5293
The interaction between serotonin (5-HT) and dopamine (DA) systems in the brain has been investigated for at least four decades. Knowledge of this subject is crucial to:
i) a better understanding of the mechanisms of action of several psychoactive drugs currently on the market and
ii) developing new monoaminergic strategies in drug design.
The precise control of midbrain DA neuronal activity and DA transmission is believed to be one cardinal feature of the treatments of neuropsychiatric diseases such as schizophrenia, Parkinson’s disease, and to a lower extent, depression, addition and drug of abuse. Therefore, our review summarizes the data regarding the action of 5-HT and its receptors on the activity of midbrain DA neurons innervating the prefrontal cortex, the nucleus accumbens and the striatum.
This interaction is extremely complex while the concepts evolve regularly. Historically, the general assumption that the 5-HT system inhibited the function of DA transmission in motor behaviors (1) led to develop neurobiological investigations aimed at understanding the action of 5-HT on midbrain DA neuronal activity (2). One open question was to know whether the 5-HT1 or the 5-HT2 receptor subtypes (3) were involved in the electrophysiological responses of DA neurons in vivo or the effects of exogenous 5-HT on 3H-DA release in vitro (4). Nowadays, none of the points raised above appear pertinent for the following reasons, going backwards:
(4) It is physiologically unsound to apply exogenous 5-HT around DA terminals in vitro or in vivo because it triggers an amphetamine-like action. The application of exogenous 5-HT does not respect the anatomo-functional relationships between these systems and the use of pharmacological ligands did not help that much as they suffered from a lack of selectivity.
(3) Pharmacological and molecular studies have identified during the 80’s and 90’s the existence of more than 14 different 5-HT receptors. Most of them impact the function of DA neuron activity in specific conditions, being inhibitory for some of them (5-HT2C, 5-HT1A, 5-HT6), excitatory for the others (5-HT1B, 5-HT2B; 5-HT2A, 5-HT3, 5-HT4), and sometimes both (5-HT1A, 5-HT2C). Medications, drugs, experimental settings, novelty, diseases create peculiar conditions favoring the involvement of specific 5-HT receptor subtypes in the regulation of DA neuron activity. The criteria are different in the cortex, the nucleus accumbens and the striatum raising the possibility to achieve a preferential modulation of one circuit toward another
(2) The predictive value of the indexes of DA neuron activity in vitro/in vivo is rather limited as regards DA transmission and, a fortiori, behaviors and this is particularly evident in the context of the 5-HT/DA interaction. In fact, in most cases, drugs acting on 5-HT receptors may alter the activity of DA neurons without clearly altering behaviors and vice versa. In other words, and paralleling the anatomical organization of 5-HT receptors in the brain, 5-HT receptors modulate the impact of DA transmission leading to indirectly adjust DA neuron activity.
(1) An inhibitory role of the 5-HT system on DA-mediated behaviors? The 5-HT system is also excitatory on numerous DA-mediated behaviors and we are no longer convinced of the pertinence of this kind of categorization regarding this interaction.
Our review focused on all these aspects, trying to harmonizing pertinent data, discussing the limits of the techniques, reporting neurobiological mechanisms and presenting the mechanisms of action of antipsychotic, anti-Parkinsonian, antidepressant and drug of abuse. In term of drug design, there is the need to further molecular interaction between DA and 5-HT receptors, with the aim of finding new compounds acting simultaneously at distinct targets, produce biased agonists at different targets.
Nevertheless, the harder task is to figure out the functional meaning of this interaction and this cannot be achieved without using a more holistic approach, considering the whole brain. Meanwhile, the questions evolve regarding this interaction and we are still searching for the good one.
Philippe De Deurwaerdère /deurwaer(at)u-bordeaux.fr / Professeur de Neurosciences et Neuropharmacologie Université de Bordeaux Institut des Maladies Neurodégénératives UMR CNRS 5293
Dernière mise à jour le 07.07.2016
Guisepe Di Giovanni
Prof. Giuseppe Di Giovanni
Physiology & Biochemistry
Faculty of Medicine & Surgery
University of Malta