Activation and Blockade of Serotonin-4 Receptors in the Lateral Habenula Produce Antidepressant Effects in the Hemiparkinsonian Rat

Guo, Yuan; Zhang, Li; Zhang, Jin; Lv, Shu-Xuan; Du, Cheng Xue; Wang, Tao; Xie, Wen; Liu, Jian

doi:10.1159/000508680

Cited by 13 publications

(4 citation statements)

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“…miR-92a is also involved in the regulation of the transcript encoding the serotonin 5-HT4 receptor, and its downregulation observed in the LHb of WKY rats correlates with upregulation of 5-HT4 mRNA expression. Recently, it has been shown that activation or blockade of the 5-HT4 receptors in the LHb produces antidepressant effects in 6-OHDA-lesioned rats, which are related to changes in monoamines in limbic and limbic-related regions [ 36 ]. Increased biosynthesis of this receptor in WKY rats might also be interpreted as contributing to their depressive phenotype — especially in the context of studies by Vidal et al [ 37 , 38 ], who have shown that chronic administration of monoaminergic antidepressants, such as fluoxetine, paroxetine, and venlafaxine (but not reboxetine), decreased 5-HT4 receptor density in the rat brain.…”

Section: Discussionmentioning

confidence: 99%

Habenula as a Possible Target for Treatment-Resistant Depression Phenotype in Wistar Kyoto Rats

et al. 2022

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The mechanisms of treatment-resistant depression (TRD) are not clear and are difficult to study. An animal model resembling human TRD is the Wistar Kyoto rat strain. In the present study, we focused on selecting miRNAs that differentiate rats of the WKY strain from Wistar Han (WIS) rats in two divisions of the habenula, the lateral and medial (LHb and MHb, respectively). Based on our preliminary study and literature survey, we identified 32 miRNAs that could be potentially regulated in the habenula. Six miRNAs significantly differentiated WKY rats from WIS rats within the MHb, and three significantly differentiated WKY from WIS rats within the LHb. Then, we selected relevant transcripts regulated by those miRNAs, and their expression in the habenular nuclei was investigated. For mRNAs that differentiated WKY rats from WIS rats in the MHb (Cdkn1c, Htr7, Kcnj9, and Slc12a5), their lower expression correlated with a higher level of relevant miRNAs. In the LHb, eight mRNAs significantly differentiated WKY from WIS rats (upregulated Htr4, Drd2, Kcnj5, and Sstr4 and downregulated Htr2a, Htr7, Elk4, and Slc12a5). These data indicate that several important miRNAs are expressed in the habenula, which differentiates WKY rats from WIS rats and in turn correlates with alterations in the expression of target transcripts. Of particular note are two genes whose expression is altered in WKY rats in both LHb and MHb: Slc12a5 and Htr7. Regulation of KCC2 via the 5-HT7 receptor may be a potential target for the treatment of TRD.

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Section: Discussionmentioning

confidence: 99%

Habenula as a Possible Target for Treatment-Resistant Depression Phenotype in Wistar Kyoto Rats

et al. 2022

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“…Overexpression of the 5-HT 4 receptor in the medial prefrontal cortex leads to antidepressant effects [55], whereas its functional ablation throughout the brain [54] or only in the hippocampus [53] causes anxiety and mood disorders. The pharmacological modulation of the 5-HT 4 receptor located in the lateral habenula also produces antidepressant effects, via changes in monoamine levels in the prefrontal cortex and hippocampus in parkinsonian rats [56]. Yet, links have been shown between the antidepressant action of 5-HT 4 receptor agonists and mechanisms of synaptic plasticity or gene regulation in the hippocampus.…”

Section: Mood and Anxiety Disordersmentioning

confidence: 99%

The Serotonin 4 Receptor Subtype: A Target of Particular Interest, Especially for Brain Disorders

Sgambato

2024

IJMS

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In recent years, particular attention has been paid to the serotonin 4 receptor, which is well expressed in the brain, but also peripherally in various organs. The cerebral distribution of this receptor is well conserved across species, with high densities in the basal ganglia, where they are expressed by GABAergic neurons. The 5-HT4 receptor is also present in the cerebral cortex, hippocampus, and amygdala, where they are carried by glutamatergic or cholinergic neurons. Outside the central nervous system, the 5-HT4 receptor is notably expressed in the gastrointestinal tract. The wide distribution of the 5-HT4 receptor undoubtedly contributes to its involvement in a plethora of functions. In addition, the modulation of this receptor influences the release of serotonin, but also the release of other neurotransmitters such as acetylcholine and dopamine. This is a considerable asset, as the modulation of the 5-HT4 receptor can therefore play a direct or indirect beneficial role in various disorders. One of the main advantages of this receptor is that it mediates a much faster antidepressant and anxiolytic action than classical selective serotonin reuptake inhibitors. Another major benefit of the 5-HT4 receptor is that its activation enhances cognitive performance, probably via the release of acetylcholine. The expression of the 5-HT4 receptor is also altered in various eating disorders, and its activation by the 5-HT4 agonist negatively regulates food intake. Additionally, although the cerebral expression of this receptor is modified in certain movement-related disorders, it is still yet to be determined whether this receptor plays a key role in their pathophysiology. Finally, there is no longer any need to demonstrate the value of 5-HT4 receptor agonists in the pharmacological management of gastrointestinal disorders.

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“…Among the many studies that discussed the prevention and treatment of PD-related depression in the 6-OHDA-induced models, a drug intervention is the most common method. Dixipramine (Kamińska et al, 2017), Piroxicam (Santiago et al, 2014), 5-HT4R agonists (Guo et al, 2021), Reboxetine (Bonito-Oliva et al, 2014), and Fluvoxamine (Dallé et al, 2020) could improve the depression symptoms in the 6-OHDA-induced models by increasing the level of relevant neurotransmitters. Etazolate (Alzoubi et al, 2018), aqueous extract of albizia leaves (Beppe et al, 2015), 1-(7-imino-3-propyl-2, 3-dihydrothiazolo [4, 5-d] pyrimidin-6(7H)-yl)urea (IDPU; Kumari et al, 2018), hesperidin (Antunes et al, 2014) and methanol extract of cottonrose hibiscus leaves (Foyet et al, 2011) could antagonize 6-OHDA-induced PD-related depression through the antioxidant stress response.…”

Section: General State Of Pd-related Depression Induced By 6-ohdamentioning

confidence: 99%

Application of Neurotoxin-Induced Animal Models in the Study of Parkinson’s Disease-Related Depression: Profile and Proposal

Mou

Guan

Yao

et al. 2022

Front. Aging Neurosci.

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Depression can be a non-motor symptom, a risk factor, and even a co-morbidity of Parkinson’s disease (PD). In either case, depression seriously affects the quality of life of PD patients. Unfortunately, at present, a large number of clinical and basic studies focused on the pathophysiological mechanism of PD and the prevention and treatment of motor symptoms. Although there has been increasing attention to PD-related depression, it is difficult to achieve early detection and early intervention, because the clinical guidelines mostly refer to depression developed after or accompanied by motor impairments. Why is there such a dilemma? This is because there has been no suitable preclinical animal model for studying the relationship between depression and PD, and the assessment of depressive behavior in PD preclinical models is as well a very challenging task since it is not free from the confounding from the motor impairment. As a common method to simulate PD symptoms, neurotoxin-induced PD models have been widely used. Studies have found that neurotoxin-induced PD model animals could exhibit depression-like behaviors, which sometimes manifested earlier than motor impairments. Therefore, there have been attempts to establish the PD-related depression model by neurotoxin induction. However, due to a lack of unified protocol, the reported results were diverse. For the purpose of further promoting the improvement and optimization of the animal models and the study of PD-related depression, we reviewed the establishment and evaluation strategies of the current animal models of PD-related depression based on both the existing literature and our own research experience, and discussed the possible mechanism and interventions, in order to provide a reference for future research in this area.

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Activation and Blockade of Serotonin-4 Receptors in the Lateral Habenula Produce Antidepressant Effects in the Hemiparkinsonian Rat

Cited by 13 publications

References 64 publications

Habenula as a Possible Target for Treatment-Resistant Depression Phenotype in Wistar Kyoto Rats

Habenula as a Possible Target for Treatment-Resistant Depression Phenotype in Wistar Kyoto Rats

The Serotonin 4 Receptor Subtype: A Target of Particular Interest, Especially for Brain Disorders

Application of Neurotoxin-Induced Animal Models in the Study of Parkinson’s Disease-Related Depression: Profile and Proposal

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