The ability of WAY100,635 to potentiate the neurochemical and functional actions of fluoxetine is enhanced by co-administration of SB224,289, but not BRL15572.
The present study employed a combined neurochemical and behavioural approach to address the question of whether blockade of (presynaptic) 5-HT(1B) or 5-HT(1D) receptors enhances the facilitatory influence of 5-HT(1A) autoreceptor antagonism upon the actions of selective serotonin re-uptake inhibitors (SSRI). In the presence of the selective 5-HT(1A) antagonist, WAY100,635, the fluoxetine-induced increase in dialysate levels of 5-HT in the frontal cortex (FCX) of freely-moving rats was significantly potentiated. The selective 5-HT(1B) antagonist, SB224,289, likewise potentiated the increase in 5-HT levels evoked by fluoxetine. Further, administered together, WAY100,635 and SB224,289, at least additively, potentiated the influence of fluoxetine upon 5-HT levels. This effect was selective inasmuch as, either alone or together, WAY100,635 and SB224,289 did not modify the influence of fluoxetine upon FCX levels of dopamine (DA) or noradrenaline (NA) quantified in the same dialysis samples. Co-administration of SB224,289 also enhanced the ability of WAY100,635 to potentiate the induction of head-twitches (HTW) by fluoxetine. This response reflects activation of 5-HT(2A) sites in FCX and was abolished by the selective 5-HT(2A) antagonist, MDL100,907. In contrast to SB224,289, the 5-HT(1D) antagonist, BRL15572, failed to enhance the facilitatory influence of WAY100,635 upon the neurochemical or behavioural actions of fluoxetine. In conclusion, co-joint blockade of 5-HT(1B) - but not 5-HT(1D) - with 5-HT(1A) autoreceptors markedly potentiates the neurochemical and functional actions of the SSRI, fluoxetine.
Gobert
A
A
Institut de Recherches Servier, Psychopharmacology Department, 125 Chemin de Ronde, 78290, Croissy-sur-Seine, France.
Dekeyne
A
A
Millan
M J
MJ
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015314:Dialysis Solutions / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004357:Drug Synergism; D005473:Fluoxetine / Q000494:pharmacology*; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D019416:Head Movements / Q000187:drug effects; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D010881:Piperidones / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology*
D001713:Biphenyl Compounds; D015314:Dialysis Solutions; D010879:Piperazines; D010881:Piperidones; D011725:Pyridines; C108518:SB 22489G; D018490:Serotonin Agents; D013141:Spiro Compounds; D005473:Fluoxetine; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; C108532:BRL 15572; D004298:Dopamine; D009638:Norepinephrine