Review articleSerotonergic modulation of the activity of mesencephalic dopaminergic systems: Therapeutic implications
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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