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Title: Evaluation of functional effects of EMD386088, a 5-HT6 receptor agonist, in animal models of psychiatric disorders

Abstract:

Disertation presents findings of pharmacological in vitro and in vivo studies evaluating functional effects of EMD 386088, a 5-HT6 receptor ligand, after its acute, subchronic and chronic administration. The other aim of this study was the attempt to clarify mechanism of its potential antidepressant and anxiolytic activity in rats.Executed radioligand studies confirmed a high affinity of EMD 386088 toward 5-HT6 receptors, expanded data on its receptor profile and selectivity. Functional in vitro studies provided the first direct body of evidence for partial agonist activity of EMD 386088 toward 5-HT6 receptors and despite of its moderate affinity for 5-HT3 receptors, for lack of antagonist 5-HT3 activity. The obtained in vivo findings demonstrate that EMD 386088 produces specific effects characteristic of antidepressants after its acute, subchronic and chronic treatment in the forced swim test in rats and in bulbectomized rats. Its antidepressant-like activity is directly connected with stimulation of 5-HT6 receptors, and indirectly with activation of dopaminergic system via D1 and D2 receptors as well as with inhibition of dopamine reuptake. A potential antidepressant effect of EMD 386088 does not seem to be connected with serotonergic andZał. nr 1 do § 2 zarządzenia nr 45Rektora UJ z 12 czerwca 2006 rokunoradrenergic innervations. EMD 386088 administered jointly with imipramine, reboxetine, moclobemide and bupropion, but not with S-citalopram, facilitates anti-immobility effects of antidepressants in the forced swim test in rats. These results may suggest possibility of a synergistic interaction between a partial agonist of 5-HT6 receptors and antidepressants which mechanism of action is connected with stimulation of dopaminergic and noradrenergic, but not serotonergic, activity.EMD 386088, after acute administration, produces specific effects characteristic of anxiolytic drugs studied in the conflict drinking Vogel and elevated plus-maze tests in rats. Mechanism of this action seems to be directly connected with stimulation of 5-HT6 receptors; however, a contribution of GABAA/benzodiazepine receptor complex should be excluded what has been confirmed by lack of GABAA receptor affinity of EMD 386088 as well as lack of functional interaction between EMD 386088 and diazepam. Moreover, antidepressant-like activity of EMD 386088 has been presented in a higher dose than its anxiolytic-like effects what may suggest different mechanisms involved in its actions.The obtained results increase our knowledge about the role of 5-HT6 receptors. They constitute an important contribution to studies concerning functional importance of agonists/partial agonists of these receptors as a basis for further, more extensive preclinical evaluation. Moreover, they confirm the desirability of testing compounds that are ligands for 5-HT6 receptors as a therapeutic target in the search for new drugs and/or extending the possibility of combination therapy of mental illnesses, primarily including depression.

Place of publishing:

Kraków

Level of degree:

2 - studia doktoranckie

Degree discipline:

farmakologia ; psychiatria

Degree grantor:

Uniwersytet Jagielloński. Collegium Medicum. Wydział Farmaceutyczny. Zakład Farmacji Klinicznej.

Promoter:

Anna Wesołowska

Date issued:

2013

Format:

application/pdf

Identifier:

oai:dl.cm-uj.krakow.pl:3618

Call number:

ZB-119054

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Language:

pol

Access rights:

tylko w bibliotece

Location of original object:

Biblioteka Medyczna Uniwersytetu Jagiellońskiego- Collegium Medicum

Object collections:

Last modified:

Jun 26, 2019

In our library since:

Nov 5, 2013

Number of object content hits:

11

Number of object content views in PDF format

10

All available object's versions:

http://dl.cm-uj.krakow.pl:8080/publication/3618

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ZB-119054 Jun 26, 2019
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