Serotonin/dopamine interaction: Electrophysiological and neurochemical evidence

doi:10.1016/bs.pbr.2021.02.001

Progress in Brain Research

Volume 261, 2021, Pages 161-264

https://doi.org/10.1016/bs.pbr.2021.02.001 Get rights and content

Abstract

The interaction between serotonin (5-HT) and dopamine (DA) in the central nervous system (CNS) plays an important role in the adaptive properties of living animals to their environment. These are two modulatory, divergent systems shaping and regulating in a widespread manner the activity of neurobiological networks and their interaction. The concept of one interaction linking these two systems is rather elusive when looking at the mechanisms triggered by these two systems across the CNS. The great variety of their interacting mechanisms is in part due to the diversity of their neuronal origin, the density of their fibers in a given CNS region, the distinct expression of their numerous receptors in the CNS, the heterogeneity of their intracellular signaling pathway that depend on the cellular type expressing their receptors, and the state of activity of neurobiological networks, conditioning the outcome of their mutual influences. Thus, originally conceptualized as inhibition of 5-HT on DA neuron activity and DA neurotransmission, this interaction is nowadays considered as a multifaceted, mutual influence of these two systems in the regulation of CNS functions. These new ways of understanding this interaction are of utmost importance to envision the consequences of their dysfunctions underlined in several CNS diseases. It is also essential to conceive the mechanism of action of psychotropic drugs directly acting on their function including antipsychotic, antidepressant, antiparkinsonian, and drug of abuse together with the development of therapeutic strategies of Alzheimer's diseases, epilepsy, obsessional compulsive disorders. The 5-HT/DA interaction has a long history from the serendipitous discovery of antidepressants and antipsychotics to the future, rationalized treatments of CNS disorders.

Introduction

Serotonin (5-HT) and dopamine (DA) systems interact in the nervous system of multiple organisms across the animal kingdom. The importance of this interaction has been revealed by the analysis of the mechanisms of action of numerous psychotropic drugs including antipsychotics and antidepressant drugs in the treatment of schizophrenia or depression (De Deurwaerdère and Di Giovanni, 2017; Di Giovanni et al., 2008). Thereafter, some pathophysiological data showed alterations in one or the other system or both in neurodegenerative diseases. While the evidence of their interaction was growing over the decades, the neurobiological context was moving with a better description of their neuronal pathways, the knowledge of the function of these neurons, and the discovery of numerous receptors for both neuromodulators. After years of intensive research, both systems are more than ever in the preoccupations of neurobiologists and clinicians to conceive newer treatments with drugs targeting integrative mechanisms rather than specific proteins, and to better act on the wide spectrum of symptoms characterizing the CNS diseases (Millan, 2006; Millan et al., 2015, Millan et al., 2016).

The understanding of the 5-HT/DA interaction today has greatly evolved from the search for the intimate mechanisms triggered by 5-HT along the nigrostriatal DA pathway to the consideration of a more widespread influence in the brain with specific links in each brain region. The concept of interaction between these two systems is complex and could be understood as the convergence of two neuromodulatory systems shaping and regulating the activity of central neurobiological networks. It is interfering with cognition, motor control, endocrine function, and likely participates to the personality traits and interindividual differences (Dalley et al., 2011). The combinations of their influences are therefore multiple which is well highlighted by the current understanding of the mechanisms of action of antipsychotic drugs, the antiparkinsonian drug l-DOPA, drugs of abuse, and antidepressant drugs.

The purpose of this chapter is to give a comprehensive report of this interaction mainly focused on the 5-HT mechanisms altering the activity of ascending DA pathways. We will present the anatomical basis of this interaction including the presentation of the neuroanatomical distribution of the two systems and their receptors. We will then present the electrophysiological and neurochemical evidence reporting the changes of DA neuron function in responses to the modification of 5-HT tone. Thereafter, we will focus on the influences of 5-HT receptors in considering for each of them their distribution, their impact on the activity of DA neurons in basal and activated conditions, and the contribution of these data to the development of therapeutic strategies of CNS diseases.

Section snippets

Neuroanatomical basis of the 5-HT/DA systems interaction

Monoaminergic systems diffusely innervate the brain. However, noticeable differences are characterizing the 5-HT and DA innervation. Whereas the 5-HT innervation covers the whole CNS, the DA innervation is much more heterogeneous, with a very high concentration of DA fibers in the striatum and the nucleus accumbens (NAc) and a very low concentration of terminals in the hippocampus and some cortical areas. To understand this neuroanatomical interaction, we have to consider that the biochemical

Global changes of 5-HT function upon DA neurotransmission

Different approaches have been tested to determine the impact of the 5-HT system on DA neurotransmission. More recently the chemogenetic—DREADD (Designer Receptor Exclusively Activated Designer Drug) (Valencia-Torres et al., 2017)—or optogenetic approaches (Wang et al., 2019) have been used to more selectively increase or decrease 5-HT neurons depending on the device, but it has been poorly used so far to investigate the influence of the 5-HT system on the function of DA neurotransmission.

Distribution of 5-HT_1A receptors

The 5-HT_1A receptor couples intracellular pathways via pertussis toxin (PTX)-sensitive heterotrimeric G proteins of the Gi/o family (Barnes and Sharp, 1999; Sharp and Barnes, 2020). 5-HT_1AR stimulation inhibits adenylyl cyclase activity and open K⁺ channels, playing an inhibitory role on cells expressing the receptor. The distribution of 5-HT_1A receptors, assessed using specific antibodies, radioligands, and complementary cDNA is marked by high heterogeneity in the brain. It is densely

Distribution of 5-HT_1B receptors

The 5-HT_1B receptor also couple intracellular signaling pathways via pertussis toxin-sensitive heterotrimeric G proteins of the Gi/o family (Barnes and Sharp, 1999; Millan et al., 2008). 5-HT_1B receptors are typically expressed in the basal ganglia and notably the SN, VTA, globus pallidus, striatum, NAc, STN and cortex (Domenech et al., 1997; Hamon et al., 1990; Radja et al., 1991; Sari et al., 1997, 1999). In the basal ganglia, mRNAs are expressed by striatal neurons and the protein is highly

Distribution of 5-HT_2A receptors

5-HT_2A/2B/2C receptors interact with Gαq protein, thereby activating phospholipase C (PLC) to dissociate the inositol 1,4,5-trisphosphate (IP3)-di-acylglycerol (DAG) complex into IP3 and DAG (Berg et al., 1998; Hoyer et al., 1994, 2002). Beyond this canonical pathway, all 5-HT₂ receptor subtypes have G-protein-dependent and independent effects that are specific for each subtype (De Deurwaerdere et al., 2020a).

The highest density of 5-HT_2A receptors in the brain is found in the cortical regions

Distribution of 5-HT_2B receptors

5-HT_2B receptors were initially found in the fundus stomach (5-HT_2F receptors) and were subsequently termed 5-HT_2B receptors (Hoyer et al., 1994). They have similar pharmacology to 5-HT_2A and 5-HT_2C receptors (Di Giovanni and De Deurwaerdere, 2016). Whereas 5-HT_2B receptor mRNAs were found in dog, cat, monkey and the human brain, notably at the level of the DRN, they were not found in the rat brain (Bonaventure et al., 2005; Bonhaus et al., 1995; Helton et al., 1994; Kursar et al., 1994;

Distribution of 5-HT_2C receptors

The 5-HT_2C receptor is one of the most complex 5-HT receptors due to the multiple described isoforms, regulatory mechanisms of expression, intracellular signaling pathways (Di Giovanni and De Deurwaerdere, 2016; Sharp and Barnes, 2020). Briefly, pre-transcriptional action leads to two different splice variants, one being the main source of several functional isoforms whereas the other one gives a truncated version of the receptor. Impressively, the coding sequence of the mRNA of the functional

Distribution of 5-HT₃ receptors

The 5-HT₃ receptor has some analogy with the nicotinic receptors. It is a cation ion channel composed of five subunits. The HT_3A–E genes correspond to the five possible subunits that have been cloned (Barnes et al., 2009; Niesler et al., 2008; Sharp and Barnes, 2020). The newer cloned subunits of the 5-HT_3C–E receptor are found in several mammals but not in rodents (Holbrook et al., 2009). The inherent molecular diversity associated with the assembly of these subunits is still not known (Abad

Distribution of 5-HT₄ receptors

The 5-HT₄ receptor was initially discovered in the brain as a “non-classical 5-HT receptor positively coupled to adenylate cyclase” (Bockaert et al., 1990; Dumuis et al., 1988b; Hoyer et al., 1994) and displayed to some extent pharmacology shared with the 5-HT₃ receptor (Dumuis et al., 1988a). The 5-HT₄ receptor has been cloned in 1995 (Gerald et al., 1995) and various slice variants [5-HT_4a–4l] have been isolated (Vilaro et al., 2005a). Beyond the canonical activation of cAMP production and

Distribution of 5-HT₆ receptors

5-HT₆ receptors have been cloned by two groups in 1993 (Monsma et al., 1993; Ruat et al., 1993). It corresponds to a GPCR. Initially considered as positively coupled to Gs, it is associated with multiple distinct partners beyond Gs including Ca^2 + signaling, Erk1/2 kinase, Cdk5, mTor, and several other partners (Chaumont-Dubel et al., 2020; Deraredj Nadim et al., 2016; Duhr et al., 2014; Riccioni et al., 2011). The distribution of 5-HT₆ receptors indicated that their binding density is elevated

Conclusion

The regulation of DA systems by 5-HT has been the subject of debate for several decades. The data reported here support, in a general sense, the long-standing notion of DA–5-HT opponency. Nevertheless, the complexity of this interaction calls for a refinement of this view. Although DA and 5-HT are tightly related and have a similar degree of functional importance, compared with DA, we have a much less specific understanding of the mechanisms by which 5-HT affects behavior.

Multiple controls of

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Chapter 4 - Serotonin/dopamine interaction: Electrophysiological and neurochemical evidence

Abstract

Introduction

Section snippets

Neuroanatomical basis of the 5-HT/DA systems interaction

Global changes of 5-HT function upon DA neurotransmission

Distribution of 5-HT1A receptors

Distribution of 5-HT1B receptors

Distribution of 5-HT2A receptors

Distribution of 5-HT2B receptors

Distribution of 5-HT2C receptors

Distribution of 5-HT3 receptors

Distribution of 5-HT4 receptors

Distribution of 5-HT6 receptors

Conclusion

Biomed. Pharmacother.

Neuropharmacology

Neuropharmacology

Neuropharmacology

Pharmacol. Ther.

Trends Neurosci.

Eur. Neuropsychopharmacol.

Eur. J. Pharmacol.

Neuropharmacology

Neuropharmacology

Neuropharmacology

Prog. Neurobiol.

Trends Pharmacol. Sci.

J. Chem. Neuroanat.

Eur. J. Pharmacol.

Neuropharmacology

Neuroscience

Neurosci. Res.

Trends Neurosci.

Trends Pharmacol. Sci.

Neuropsychopharmacology

Brain Res.

Eur. J. Pharmacol.

Neuropharmacology

Neuropharmacology

Rev. Neurol. (Paris)

Neuron

Neuroscience

Prog. Brain Res.

Neuroscience

Pharmacol. Biochem. Behav.

Alcohol

Eur. J. Pharmacol.

Neuroscience

Exp. Neurol.

Neuropharmacology

Impact of serotonin 2C receptor null mutation on physiology and behavior associated with nigrostriatal dopamine pathway function

J. Neurosci.

Sulpiride in combination with fluvoxamine increases in vivo dopamine release selectively in rat prefrontal cortex

Neuropsychopharmacology

Modulation of dopamine release by striatal 5-HT2C receptors

Synapse

Co-expression and in vivo interaction of serotonin1A and serotonin2A receptors in pyramidal neurons of prefrontal cortex

Cereb. Cortex

VGLUT3 (vesicular glutamate transporter type 3) contribution to the regulation of serotonergic transmission and anxiety

J. Neurosci.

Functional status of the serotonin 5-HT2C receptor (5-HT2CR) drives interlocked phenotypes that precipitate relapse-like behaviors in cocaine dependence

Neuropsychopharmacology

Serotonin (5-HT) 5-HT2A receptor (5-HT2AR):5-HT2CR imbalance in medial prefrontal cortex associates with motor impulsivity

ACS Chem. Neurosci.

Ritanserin potentiates the stimulatory effects of raclopride on neuronal activity and dopamine release selectivity in the mesolimbic dopaminergic system

Naunyn-Schmiedebergs Arch. Pharmacol.

The 5-HT1A receptor selective ligands, (R)-8-OH-DPAT and (S)-UH-301, differentially affect the activity of midbrain dopamine neurons

Naunyn-Schmiedebergs Arch. Pharmacol.

Mechanism of action of antidepressants

Psychopharmacol. Bull.

Contrasting contribution of 5-hydroxytryptamine 1A receptor activation to neurochemical profile of novel antipsychotics: frontocortical dopamine and hippocampal serotonin release in rat brain

J. Pharmacol. Exp. Ther.

F15599, a highly selective post-synaptic 5-HT(1A) receptor agonist: in-vivo profile in behavioural models of antidepressant and serotonergic activity

Int. J. Neuropsychopharmacol.

Locus coeruleus, A5 and A7 noradrenergic cell groups

Role of serotonin 2A receptors in the D-amphetamine-induced release of dopamine: comparison with previous data on alpha1b-adrenergic receptors

J. Neurochem.

Distribution of 5-HT_1A receptors

Distribution of 5-HT_1B receptors

Distribution of 5-HT_2A receptors

Distribution of 5-HT_2B receptors

Distribution of 5-HT_2C receptors

Distribution of 5-HT₃ receptors

Distribution of 5-HT₄ receptors

Distribution of 5-HT₆ receptors