Study of a mechanism responsible for potential antidepressant activity of EMD 386088, a 5-HT6 partial agonist in rats

• Published in: Naunyn-Schmiedeberg's archives of pharmacology Vol. 389; no. 8; pp. 839 - 849
• Main Authors: Jastrzębska-Więsek, Magdalena, Siwek, Agata, Partyka, Anna, Antkiewicz-Michaluk, Lucyna, Michaluk, Jerzy, Romańska, Irena, Kołaczkowski, Marcin, Wesołowska, Anna
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-08-2016
• Subjects: Animals; Antidepressive Agents - pharmacology; Behavior, Animal - drug effects; Biomedical and Life Sciences; Biomedicine; Brain - drug effects; Brain - metabolism; CHO Cells; Cricetulus; Depression - drug therapy; Depression - metabolism; Depression - psychology; Disease Models, Animal; Dopamine - metabolism; Dopamine Agonists - pharmacology; Dopamine D2 Receptor Antagonists - pharmacology; Dopamine Plasma Membrane Transport Proteins - antagonists & inhibitors; Dopamine Plasma Membrane Transport Proteins - genetics; Dopamine Plasma Membrane Transport Proteins - metabolism; Dose-Response Relationship, Drug; Drug Partial Agonism; Humans; Indoles - pharmacology; Male; Motor Activity - drug effects; Neurosciences; Norepinephrine - metabolism; Original; Original Article; Pharmacology/Toxicology; Pyridines - pharmacology; Rats, Wistar; Receptors, Dopamine D1 - agonists; Receptors, Dopamine D1 - metabolism; Receptors, Dopamine D2 - agonists; Receptors, Dopamine D2 - metabolism; Receptors, Serotonin - drug effects; Receptors, Serotonin - metabolism; Serotonin - metabolism; Serotonin Receptor Agonists - pharmacology; Transfection; EMD386088; Forced swim test; Monoamines metabolism; Rats; Depression; 5-HT; receptor agonist; 5-HT6 receptor agonist
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-016-1245-3

It was shown that 5-HT
6
receptor agonists can exert pharmacological activity due to various modifications in monoamines’ level and metabolism activity in rats’ brain structures. This finding was correlated with antidepressant- or anxiolytic-like properties of these compounds. The study was designed to establish a possible mechanism of the antidepressant-like activity of the partial 5-HT
6
receptor agonist EMD386088 (5-chloro-2-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1
H
-indole hydrochloride) in rats. The concentrations of monoamines (dopamine (DA), noradrenaline (NA), and serotonin (5-HT)) and the rate of their metabolism were measured ex vivo in the brain structures (
hippocampus
,
nucleus accumbens
,
striatum
) using high-performance liquid chromatography (HPLC). The rats were killed after the forced swim test (FST); the collected tissue samples were used to ex vivo experiments. The potency of EMD386088 to blockade dopamine transporter (DAT) was tested in a functional in vitro study. FST was used to assess the involvement of D
1
- and D
2
-like receptor subfamilies in antidepressant-like properties of EMD386088. Neurochemical data from ex vivo experiments showed that antiimmobility activity of EMD386088 may be connected with the activation of dopaminergic system, while neither noradrenergic nor serotonergic ones are involved in its effect. EMD386088 also possesses a significant affinity for DAT which may be a mechanism in the abovementioned effect. Behavioral data seem to confirm the importance of dopaminergic system activation in antidepressant-like activity of EMD386088, since this effect, observed in the FST, was abolished by the preferential D
1
- and D
2
-like receptor subfamily antagonists SCH23390 and sulpiride, respectively. Dopaminergic system is involved in antidepressant-like activity of EMD386088.