Elsevier

Progress in Neurobiology

Volume 151, April 2017, Pages 175-236
Progress in Neurobiology

Review article
Serotonergic modulation of the activity of mesencephalic dopaminergic systems: Therapeutic implications

https://doi.org/10.1016/j.pneurobio.2016.03.004Get rights and content

Highlights

  • Serotonin exerts different controls towards ascending dopamine pathways.

  • Most serotonin receptors can participate in the control of each dopamine pathway.

  • The influence of serotonin receptors on dopamine neurons is conditional in subcortical regions.

  • The 5-HT2C receptor is solely involved in inhibitory controls of basal dopamine activity.

  • Serotonin controls participate differentially in the mechanisms of psychoactive drugs.

Abstract

Since their discovery in the mammalian brain, it has been apparent that serotonin (5-HT) and dopamine (DA) interactions play a key role in normal and abnormal behavior. Therefore, disclosure of this interaction could reveal important insights into the pathogenesis of various neuropsychiatric diseases including schizophrenia, depression and drug addiction or neurological conditions such as Parkinson’s disease and Tourette’s syndrome. Unfortunately, this interaction remains difficult to study for many reasons, including the rich and widespread innervations of 5-HT and DA in the brain, the plethora of 5-HT receptors and the release of co-transmitters by 5-HT and DA neurons. The purpose of this review is to present electrophysiological and biochemical data showing that endogenous 5-HT and pharmacological 5-HT ligands modify the mesencephalic DA systems’ activity. 5-HT receptors may control DA neuron activity in a state-dependent and region-dependent manner. 5-HT controls the activity of DA neurons in a phasic and excitatory manner, except for the control exerted by 5-HT2C receptors which appears to also be tonically and/or constitutively inhibitory. The functional interaction between the two monoamines will also be discussed in view of the mechanism of action of antidepressants, antipsychotics, anti-Parkinsonians and drugs of abuse.

Introduction

The interaction between serotonin (5-HT) and dopamine (DA) systems in the brain has been investigated by neurobiologists, psychiatrics, neurologists and pharmacologists for at least four decades. Knowledge of this subject seems crucial to a better understanding of the mechanisms of action of several psychoactive drugs currently on the market, but especially to drug discovery. The field of antipsychotic drugs is probably a good illustration of the pertinence of the 5-HT/DA interaction in drug design. Notably, the therapeutic benefit of atypical antipsychotics in terms of fewer extrapyramidal side effects and larger efficacy in reducing psychosis has been related to their ability to block 5-HT2A receptors more efficiently with respect to DA-D2 receptors (Deutch et al., 1991, Meltzer, 1999a, Meltzer and Huang, 2008). Although this property is still a matter of debate, such a consideration has raised great interest regarding the contribution of the 5-HT system in the mechanism of action of DA drugs in humans. Nowadays, the other pharmacological properties of these atypical antipsychotic drugs (i.e., 5-HT1A, 5-HT2C, 5-HT3, 5-HT6 affinity) have been studied and have led to a better knowledge of the 5-HT/DA interaction. Similarly, a closer look at the mechanism of action of drugs of abuse and dopaminomimetics has disclosed several pieces of information on this interaction. In particular, the best medication in Parkinson’s disease (PD) for almost 50 years has been the exogenous administration of the metabolic precursor of DA, L-3,4-dihydroxyphenylalanine (L-DOPA). An increasing body of evidence indicates that 5-HT neurons directly and indirectly mediate the actions of L-DOPA, leading to the development of 5-HT-based compounds to counteract the unwanted motor, mood and psychotic outcomes of L-DOPA therapy (Bastide et al., 2015, Carta et al., 2007, Carta et al., 2008, Jenner et al., 1983, Melamed et al., 1996, Pact and Giduz, 1999, Zoldan et al., 1996). The influence of the 5-HT system in the control of DA neuron activity appears as a pivotal factor in the motor, mood and cognitive effects of DA therapies.

The precise nature of the interactions between 5-HT and DA has been difficult to elucidate, in that both inhibitory and excitatory roles for 5-HT have been suggested and shown (Di Giovanni et al., 2008b, Fink and Gothert, 2007, Kapur and Remington, 1996, Soubrie et al., 1984). The discrepancies among the studies are related to the numerous parameters studied, the existence of 5-HT responses mediated or not by 5-HT receptors, the existence of several 5-HT receptor subtypes (Di Matteo et al., 2008a, Navailles and De Deurwaerdere, 2011) and the release of other co-transmitters (Trudeau, 2004). In addition, the interaction between the two monoaminergic systems appears to be region-dependent (Fitoussi et al., 2013) and is likely to involve other neurotransmitter systems (Guiard et al., 2008).

In order to review the 5-HT modulation upon DA systems, we will first describe the anatomy of the 5-HT system in brain regions innervated by DA neurons. Then, we will show the electrophysiological data demonstrating the influence of 5-HT neurons and 5-HT receptors on the activity of mesencephalic DA neurons. Thereafter, we will report the biochemical evidence supporting an interaction of 5-HT on DA function. This will delineate the widespread influences of the 5-HT systems toward many aspects of the biochemistry of the DA neuron. Finally, the electrophysiological and biochemical findings will be used to decipher the mechanism of action of numerous classes of psychoactive drugs including antidepressants, antipsychotics, antiparkinsonians (mostly L-DOPA) and drugs of abuse. The pitfalls and limits of these two experimental techniques will also be critically discussed.

Section snippets

The anatomy and physiology of the DA and 5-HT systems

The brain is made of networks of neurons and monoaminergic systems that innervate in a diffuse and rich manner. All brain areas receive a 5-HT innervation that is quantitatively quite homogeneous. Conversely, DA innervation is inhomogeneous and dramatically more pronounced in some brain regions, including the caudate putamen (striatum), different cortices such as the olfactory tubercle and the lateral hypothalamus. DA is barely detectable in many other brain regions. It is thus logical that the

Effect of 5-HT on DA neuron activity

The first in vivo recordings from neurochemically identified DA-containing neurons in the SNc and VTA of anaesthetized rats were performed by Bunney and colleagues at Yale University in the 1970s (Bunney et al., 1973a, Bunney et al., 1973b). 5-HT was one of the first neurotransmitters investigated as a modulator of DA electrical activity. Its microiontophoretic application produced only a weak inhibition of the firing rate of VTA DA neurons (Aghajanian and Bunney, 1974). On the other side of

Biochemical influences of 5-HT on tissue DA contents

The impact of the 5-HT system on the biochemical activity of DA neuron has been studied using many approaches, including tissue measurement. In particular, it has been reported that the lesion of 5-HT neurons may increase the DA (the ratio DOPAC/DA) turnover in the striatum (Le Moal and Simon, 1991). This effect has not been systematically reported (De Deurwaerdere et al., 1995, De Deurwaerdere et al., 1998, Soubrie et al., 1984) while the data is sporadic. There are some differences in the

Antidepressant drugs

DA has received little attention in anxiety and depression as compared to other monoamines such as 5-HT and NE. The role of DA in mood disorders results perhaps from the complexity of brain organization in mammals because it relies preferentially on 5-HT rather than DA systems in other species like crayfish (Fossat et al., 2014; 2015). In mammals, it also implies that the impact of 5-HT on DA release in the mechanism of action of anxiolytic/antidepressant drugs is not well known. Yet, it is

Conclusions

5-HT and DA systems are closely related in the CNS, and involvement of 5-HT receptors in the regulation of central DA activity is now well established. We have reported here electrophysiological and biochemical data, showing the impact of the 5-HT and its ligands on the DA systems. We have highlighted various discrepancies and have identified numerous pharmacological biases that complicate the analysis of this interaction. After this analysis, we propose that the impact of the 5-HT system on DA

Acknowledgments

The authors are indebted to the EU COST Action CM1103 “Structure-based drug design for diagnosis and treatment of neurological diseases: dissecting and modulating complex function in the monoaminergic systems of the brain” for supporting their international collaboration. We wish to thank Dr Mélanie Lagière for help with editing.

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