In vivo evidence that 5-HT(2C) receptors inhibit 5-HT neuronal activity via a GABAergic mechanism.

Full Abstract

BACKGROUND

AND PURPOSE:
Recent evidence suggests that 5-HT(2C) receptor activation may inhibit midbrain 5-HT neurones by activating neighbouring GABA neurones. This hypothesis was tested using the putative selective 5-HT(2C) receptor agonist, WAY 161503.

EXPERIMENTAL APPROACH:
The effect of WAY 161503 on 5-HT cell firing in the dorsal raphe nucleus (DRN) was investigated in anaesthetised rats using single unit extracellular recordings. The effect of WAY 161503 on DRN GABA neurones was investigated using double label immunohistochemical measurements of Fos, glutamate decarboxylase (GAD) and 5-HT(2C) receptors. Finally, drug occupancy at 5-HT(2A) receptors was investigated using rat positron emission tomography and ex vivo binding studies with the 5-HT(2A) receptor radioligand [(11)C]MDL 100907.

KEY RESULTS:
WAY 161503 caused a dose-related inhibition of 5-HT cell firing which was reversed by the 5-HT(2) receptor antagonist ritanserin and the 5-HT(2C) receptor antagonist SB 242084 but not by the 5-HT(1A) receptor antagonist WAY 100635. SB 242084 pretreatment also prevented the response to WAY 161503. The blocking effects of SB 242084 likely involved 5-HT(2C) receptors because the drug did not demonstrate 5-HT(2A) receptor occupancy in vivo or ex vivo. The inhibition of 5-HT cell firing induced by WAY 161503 was partially reversed by the GABA(A) receptor antagonist picrotoxin. Also, WAY 161503 increased Fos expression in GAD positive DRN neurones and DRN GAD positive neurones expressed 5-HT(2C) receptor immunoreactivity.

CONCLUSIONS AND IMPLICATIONS:
These findings indicate that WAY 161503 inhibits 5-HT cell firing in the DRN in vivo, and support a mechanism involving 5-HT(2C) receptor-mediated activation of DRN GABA neurones.

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Author information

Author/s: Boothman, L (L); Raley, J (J); Denk, F (F); Hirani, E (E); Sharp, T (T);

Affiliation: University Department of Pharmacology, Oxford, UK.

Grants: (Agency:Wellcome Trust)

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: British journal of pharmacology (Br J Pharmacol), published in England. (Language: eng)

Reference: 2006-Dec; vol 149 (issue 7) : pp 861-9

Dates: Created 2006/11/27; Completed 2007/02/02; Revised 2008/11/20;

PMID: 17043669, status: MEDLINE (last retrieval date: 12/26/2008)

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Action Potentials - drug effects
Aminopyridines - pharmacology
Animals
Brain Chemistry - drug effects
Dopamine Agonists - metabolism; pharmacology
Dopamine Antagonists - pharmacology
Dose-Response Relationship, Drug
GABA Antagonists - pharmacology
Glutamate Decarboxylase - analysis
Immunohistochemistry
Indoles - pharmacology
Male
Neural Inhibition - drug effects
Neurons - chemistry; drug effects; metabolism

Picrotoxin - pharmacology
Piperazines - pharmacology
Positron-Emission Tomography
Proto-Oncogene Proteins c-fos - analysis
Pyrazines - metabolism; pharmacology
Pyridines - pharmacology
Quinoxalines - metabolism; pharmacology
Raphe Nuclei - chemistry; cytology; drug effects; metabolism
Rats
Rats, Sprague-Dawley
Receptor, Serotonin, 5-HT2C - analysis; drug effects; metabolism
Ritanserin - pharmacology
Serotonin - metabolism
gamma-Aminobutyric Acid - metabolism

Associated Chemicals: 8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino(1,2-a)quinoxalin-5(6H)-one (0) ; Aminopyridines (0) ; Dopamine Agonists (0) ; Dopamine Antagonists (0) ; GABA Antagonists (0) ; Indoles (0) ; Piperazines (0) ; Proto-Oncogene Proteins c-fos (0) ; Pyrazines (0) ; Pyridines (0) ; Quinoxalines (0) ; Receptor, Serotonin, 5-HT2C (0) ; SB 242084 (0) ; Picrotoxin (124-87-8) ; WAY 100635 (146714-97-8) ; Serotonin (50-67-9) ; gamma-Aminobutyric Acid (56-12-2) ; Ritanserin (87051-43-2) ; Glutamate Decarboxylase (EC 4.1.1.15)

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