Implication of 5-HT2 receptor subtypes in the mechanism of action of antidepressants in the four plates test.
BACKGROUND
The selective serotonin reuptake inhibitors (SSRIs) and the serotonin and noradrenaline reuptake inhibitors (SNRIs) increase synaptic levels of serotonin, leading to an increased activation of a multitude of specific postsynaptic 5-HT receptors. However, it is not yet known which 5-HT receptor subtypes mediate the therapeutic effects of antidepressants.


METHODS
The effects of the SSRI, paroxetine and the SNRI, venlafaxine were evaluated in the mouse four plates test (FPT).


RESULTS
Paroxetine administered intraperitoneally (IP) (0.5, 2-8 mg/kg) potently augmented the number of punished passages accepted by mice in this paradigm. The effects of paroxetine (8 mg/kg) were not reversed by the selective 5-HT2C receptor antagonist, RS 10-2221 (0.1 mg/kg and 1 mg/kg) or the selective 5-HT2B/2C receptor antagonist SB 206553 (0.1 mg/kg and 1 mg/kg), at doses which lack an effect when administered alone. In contrast, the selective 5-HT2A receptor antagonist, SR 46349B (0.1 mg/kg and 1 mg/kg) completely abolished the paroxetine-induced increase in punished passages. The acute administration of venlafaxine induced an anxiolytic-like effect in the FPT at the doses of 2-16 mg/kg. This effect was reversed by the 5-HT2B/2C receptor antagonist as did SR 46349B, for both doses administered. Our results strongly suggest that activation of 5-HT2A receptors is critically involved in the anxiolytic activity of paroxetine, whereas the 5-HT2A and 5-HT2B receptors are involved in the anti-punishment action of venlafaxine in the FPT. The co-administration of selective 5-HT2A, 2B, 2C receptor agonists (DOI, 0.06 mg/kg and 0.25 mg/kg; BW 723C86, 0.5 mg/kg and 2 mg/kg and RO 60-0175, 0.06 mg/kg and 0.25 mg/kg), respectively, was subsequently investigated. The effects of sub-active doses of paroxetine (0.25 mg/kg and 1 mg/kg) were augmented by BW 723C86 and RO 60-0175 receptor agonist challenge. The anti-punishment effects of venlafaxine (0.25 mg/kg and 1 mg/kg) were potentialised only by DOI co-administration.


CONCLUSIONS
These results indicate that the co-administration of 5-HT2 receptor agonists with paroxetine and venlafaxine may provide a powerful tool for enhancing the clinical efficacy of these antidepressants.
Nic Dhonnchadha
Bríd Aine
BA
EA 3256, Neurobiologie de l'anxiété et de la dépression, Faculté de Médecine, BP 53508, 1 rue Gaston Veil, 44035 Nantes Cedex 01, France.
Ripoll
Nadège
N
Clénet
Florence
F
Hascoët
Martine
M
Bourin
Michel
M
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects*; D003511:Cyclohexanols / Q000494:pharmacology; D004597:Electroshock; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D017374:Paroxetine / Q000494:pharmacology; D011678:Punishment; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects*; D044403:Receptor, Serotonin, 5-HT2B / Q000187:drug effects*; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects; D011963:Receptors, GABA-A / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013268:Stimulation, Chemical; D000069470:Venlafaxine Hydrochloride
D000928:Antidepressive Agents; D003511:Cyclohexanols; D006993:Hypnotics and Sedatives; D017374:Paroxetine; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011963:Receptors, GABA-A; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride