F15599, a preferential post-synaptic 5-HT1A receptor agonist: activity in models of cognition in comparison with reference 5-HT1A receptor agonists.
We assessed the activity of F15599, a selective and high efficacy 5-HT(1A) agonist that preferentially activates post- versus pre-synaptic receptors, in rat cognition/memory models. F15599 (0.16 mg/kg i.p.) partially alleviated detrimental effects of phencyclidine on working and reference memory deficit in a hole-board model. It also attenuated phencyclidine-induced deficit of cognitive flexibility in a reversal learning task, without effects of its own. F13714 (0.04 mg/kg) a chemical congener of F15599, and 8-OH-DPAT (0.01 or 0.16), were inactive against these phencyclidine-induced deficits, and/or even worsened basal performances. F15599 (0.04-2.5) was less disruptive than F13714 (0.005-0.16) or 8-OH-DPAT (0.01-0.63), on basal performance in models of attention (5-choice serial reaction time task) and working memory (delayed non-matching to position). Finally, unlike either comparator, F15599 reduced PPI with modest potency and only partially. To conclude, F15599, in models of memory/cognition, has a more favourable profile than F13714 and 8-OH-DPAT. This suggests that preferential activation of post-synaptic 5-HT(1A) receptors could prove useful in pathologies characterized by cognitive/memory deficiencies, such as schizophrenia and depression.
Depoortère
Ronan
R
Neurobiology 2 Division, Centre de Recherche Pierre Fabre, 17, avenue Jean Moulin, 81106 Castres, France. ronan.depoortere@pierre-fabre.com
Auclair
Agnès L
AL
Bardin
Laurent
L
Colpaert
Francis C
FC
Vacher
Bernard
B
Newman-Tancredi
Adrian
A
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism / Q000494:pharmacology; D000631:Aminopyridines / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D010622:Phencyclidine / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*; D015398:Signal Transduction
C119079:3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methyl-6-methylaminopyridin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone; C524188:3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methylpyrimidin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone; D000631:Aminopyridines; D004791:Enzyme Inhibitors; D010880:Piperidines; D011743:Pyrimidines; D058825:Serotonin 5-HT1 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D010622:Phencyclidine