title: Divergent effects of the 'biased' 5-HT1 A receptor agonists F15599 and F13714 in a novel object pattern separation task.
abstract: OBJECTIVE
  Pattern separation, that is, the formation of distinct representations from similar inputs, is an important hippocampal process implicated in cognitive domains like episodic memory. A deficit in pattern separation could lead to memory impairments in several psychiatric and neurological disorders. Hence, mechanisms by which pattern separation can be increased are of potential therapeutic interest.
  
  
  METHODS
  5-HT1A receptors are involved in spatial memory. Herein we tested the 'biased' 5-HT1A receptor agonists F15599, which preferentially activates post-synaptic heteroreceptors, and F13714, which preferentially activates raphe-located autoreceptors, in rats in a novel spatial task assessing pattern separation, the object pattern separation (OPS) task.
  
  
  RESULTS
  The acetylcholinesterase inhibitor donepezil, which served as a positive control, significantly improved spatial pattern separation at a dose of 1 mg·kg(-1) , p.o. F15599 increased pattern separation at 0.04 mg·kg(-1) , i.p., while F13714 decreased pattern separation at 0.0025 mg·kg(-1) , i.p. The selective 5-HT1A receptor antagonist WAY-100635 (0.63 mg·kg(-1) , s.c.) counteracted the effects of both agonists. These data suggest that acute preferential activation of post-synaptic 5-HT1A heteroreceptors improves spatial pattern separation, whereas acute preferential activation of raphe-located 5-HT1A autoreceptors impairs performance.
  
  
  CONCLUSIONS
  We successfully established and validated a novel, simple and robust OPS task and observed a diverging profile of response with 'biased' 5-HT1A receptor agonists based on their targeting of receptors in distinct brain regions. Our data suggest that the post-synaptic 5-HT1A receptor consists of a potential novel molecular target to improve pattern separation performance.
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors.forename: N P
authors.initials: NP
authors.lastname: van Goethem
authors.forename: R
authors.initials: R
authors.lastname: Schreiber
authors.forename: A
authors.initials: A
authors.lastname: Newman-Tancredi
authors.forename: M
authors.initials: M
authors.lastname: Varney
authors.forename: J
authors.initials: J
authors.lastname: Prickaerts
mesh_terms: D000631:Aminopyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007189:Indans / Q000494:pharmacology; D008297:Male; D010364:Pattern Recognition, Visual / Q000187:drug effects* / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology
chemical_list: 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; D007189:Indans; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D011743:Pyrimidines; D058825:Serotonin 5-HT1 Receptor Agonists; D012702:Serotonin Antagonists; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D000077265:Donepezil