Hmm, at a 8 mg/kg pi comparison across all in the swiss mice. The species comparison/ differences in the discussion was curious.
Perhaps the venlafaxine was underdosed for NA affinity / effects. This study
The present study was undertaken to investigate thoroughly the preclinical psychopharmacological profile of venlafaxine, testing a wide range of doses in animal models indicative of antidepressant-like effects. Venlafaxine was found to be active in mouse forced swimming test (at 8, 16, 32 and 64...
pubmed.ncbi.nlm.nih.gov
Shows increased locomotor act at 16 mg kg +, the dose dependency. (Maybe the DAT and other effects even higher.
Paroxetine doesn't seem too too surprising, given pretty strong NET affinity (though not near its picomolar SERT). But by that flawed logic paroxetine at about 150 nM Ki would be more relevant than dextromethylphenidate at ~200 nM Ki (didn't look up IC50 and activity for paroxetine) . Versus 2500 nM Ki for VFX (IC50 ~500 nM).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527955/ could be decent to follow up relevant net affinity/activity per dose. Paroxetine had lower nM Ki for NET than VFX.
Now citalopram, that is different. Doesn't have the NET affinity and is relatively selective. And this is the frontal cortex. Maybe at that dose there is some relevance to citalopram 5-ht2c activity? Certainly not like fluoxetine, functionally or in affinity, but that might be part behind 5-ht2c frontal partial regulation of DA and NE. Still, doesn't seem quite enough...
Some pure serotonergic effect seems less likely due to high VFX activity there.
(Staying away from sigma nonsense (say citalopram vs sertraline) or neurosteroid effects.)
Interesting study.
But yeah, I could imagine taking 150 mg paroxetine vs 150 mg venlafaxine might highlight some of paroxetine's lesser affinities, in addition to SERT. Muscarinic fun.
