Review article
The role of serotonergic, adrenergic and dopaminergic receptors in antidepressant-like effect

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Abstract

Depression is a serious global illness, becoming more and more common in developed countries. Because of specific symptoms it is considered as a leading cause of disability all over the world with a high death factor due to suicides. There are many antidepressants used in the therapy, but still more than 30% of patients do not respond to the treatment. The heterogeneous nature of the illness and its complex, unclear aetiology may be responsible for these difficulties. Next to the main monoaminergic hypothesis of depression there are also many other approaches connected with the pathophysiology of the disease, including hypothalamic–pituitary–adrenal axis dysregulation, dopaminergic, cholinergic, glutamatergic or GABA-ergic neurotransmission. Nevertheless, it can be unambiguously stated that serotonergic, noradrenergic and dopaminergic systems are precisely connected with pathogenesis of depression, and should be therefore considered as valuable targets in patients’ treatment. Bearing that in mind, this review presents the role of serotonergic, adrenergic and dopaminergic receptors in antidepressant-like effect.

Introduction

Major depressive disorder (MDD) is common and serious problem in modern society, and is responsible for disability worldwide. Sadness, lost of interest or pleasure, disturbed sleep and appetite, feelings of tiredness, low self-esteem or poor concentration are one of the main depressive symptoms, which strongly impair the individual's ability to function or cope with daily life, and sometimes can even lead to suicide. Currently one in four people in the world is affected by depression [1]. It is assumed that until 2020 it will be the second most commonly diagnosed disease in the world, just after ischaemic heart disease [1]. Despite the fact that there are many available antidepressants and possible therapies, there is still a problem with the efficacy of the treatment. It is very likely that this problem is associated with the complexity, and still not fully understood pathomechanism of the disease.

Since 1965 the monoaminergic theory of depression was considered as the main and only cause of the illness. This hypothesis assumed that MDD is connected with serotonin (5-hydroxytryptamine; 5-HT) and noradrenaline (norepinephrine; NA) deficits in different parts of the brain, and therefore the enhancement of serotonergic and noradrenergic neurotransmission, will result in the improvement of the common symptoms of the disease [2]. Over the years this theory has evolved, and many new approaches appeared. Scientists noticed the strong relationship between depressive state and changes in various systems not only serotonergic and noradrenergic but also dopaminergic, cholinergic, glutamatergic, GABA-ergic or hypothalamic–pituitary–adrenal (HPA) axis dysregulation. This review will discuss the role and involvement of serotonergic, adrenergic and dopaminergic receptors in antidepressant-like (AD-like) effect.

Section snippets

Animal tests and models of depression

First and foremost, it should be clarified that there is a difference between a test and a model of depression. A model includes both an independent variable (induced manipulation), and a dependent variable (behavioural/neurochemical readout), while a test simply comprises the latter variable [3], [4].

There are two commonly used tests to assess AD-like activity – forced swim test (FST) and tail suspension test (TST). Both are based on the observation that when rodents are subjected to an

Serotonergic system

Fluoxetine, the first selective 5-HT reuptake inhibitor (SSRI) was introduced in 1987 and its unique properties, appropriate clinical efficacy, and lower toxicity in comparison with the monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) overshadowed the previous pharmacological strategies, and emphasized the role of 5-HT in the MDD [33]. 5-HT is a monoamine neurotransmitter, which receptors emerged in the early stages of embryogenesis, and are distributed widespread in

5-HT1A receptors

Accumulating data have shown that agonists and antagonists of the 5HT1A receptors, as well as genetically modified mice lacking this subtype of receptor demonstrated AD-like activity in the several rodent tests and models of depression [20]. Agonists and even partial agonists of 5-HT1A produced AD-like effects after chronic administration, e.g. flesixonan in OB, buspirone in the CMS, 8-OH-DPAT and buspirone in the FST (in rats), VN2222 in the LH paradigm [61], [62], [63]. It is believed that

The role of the ionotropic 5-HT3 receptors in AD-like effect

A large body of evidence demonstrated that the 5-HT3 receptor antagonists, e.g. ondansetron, dolasetron and tropisetron, produced AD-like response in several rodents tests and models of depression [24]. On the contrary, 5-HT3 agonists, reduced the action of antidepressants in the FST in rats [103]. Furthermore, it is well known that the mechanism of action of fluoxetine and other antidepressants, is connected with the non-competitive antagonism of the 5-HT3 receptor [20]. The results reported

Noradrenergic system

The noradrenergic system is also involved in the pathophysiology of depression. MDD seems to be associated with a hypofunction of the noradrenergic system at least in part, so some antidepressants act by increasing the synaptic availability of NA [108]. Adrenergic receptors (α and β subtypes) are the basic targets of endogenous neurotransmitters NA and adrenaline, especially in mediating sympathetic activation to peripheral organs, but also in central nervous system (CNS). In addition,

Dopaminergic system

DA belongs to catecholamines alongside epinephrine and NA. It is not only a precursor of the latters, but also exerts its physiological effect [40]. DA receptors are G protein-coupled ones; they are expressed, inter alia, in the CNS. Two families amongst them are distinguished: D1-like comprising D1 and D5 receptors and D2-like consisting of D2, D3 and D4 [40], [153]. D1-like receptors are coupled to the Gs protein, hence their stimulation leads to the activation of AC and biosynthesis of cAMP.

Conclusions

This review presents data on some important findings concerning the involvement of serotonergic, noradrenergic and dopaminergic receptors in AD-like effect. Based on scientific reports we were able to confirm the role and the importance of these three neurotransmission pathways in depression's aetiology. Data indicate the significant changes in the functioning and sensitivity of 5-HT, α-, β- and DA receptors in depressive patients. Moreover, many preclinical evidences clearly suggest the

Funding

This work was supported by Jagiellonian University grant number K/DSC/001955.

Conflict of interest

All the authors declare no conflict of interest.

Acknowledgement

Karolina Podkowa is a holder of scholarship from the KNOW sponsored by Ministry of Science and Higher Education, Poland.

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