title: 5-HT(6)  receptor agonists and antagonists enhance learning and memory in a conditioned emotion response paradigm by modulation of cholinergic and glutamatergic mechanisms.
abstract: OBJECTIVE
  5-HT(6) receptors are abundant in the hippocampus, nucleus accumbens and striatum, supporting their role in learning and memory. Selective 5-HT(6) receptor antagonists produce pro-cognitive effects in several learning and memory paradigms while 5-HT(6) receptor agonists have been found to enhance and impair memory.
  
  
  METHODS
  The conditioned emotion response (CER) paradigm was validated in rats. Then we examined the effect of the 5-HT(6) receptor antagonist, EMD 386088 (10 mg·kg(-1) , i.p.), and agonists, E-6801 (2.5 mg·kg(-1) , i.p.) and EMD 386088 (5 mg·kg(-1) , i.p.) on CER-induced behaviour either alone or after induction of memory impairment by the muscarinic receptor antagonist, scopolamine (0.3 mg·kg(-1) , i.p) or the NMDA receptor antagonist, MK-801 (0.1 mg·kg(-1) , i.p).
  
  
  RESULTS
  Pairing unavoidable foot shocks with a light and tone cue during CER training induced a robust freezing response, providing a quantitative index of contextual memory when the rat was returned to the shock chamber 24 h later. Pretreatment (-20 min pre-training) with scopolamine or MK-801 reduced contextual freezing 24 h after CER training, showing production of memory impairment. Immediate post-training administration of 5-HT(6) receptor antagonist, SB-270146, and agonists, EMD 386088 and E-6801, had little effect on CER freezing when given alone, but all significantly reversed scopolamine- and MK-801-induced reduction in freezing. CONCLUSION AND IMPLICATIONS Both the 5-HT(6) receptor agonists and antagonist reversed cholinergic- and glutamatergic-induced deficits in associative learning. These findings support the therapeutic potential of 5-HT(6) receptor compounds in the treatment of cognitive dysfunction, such as seen in Alzheimer's disease and schizophrenia.
authors.affiliation: School of Biomedical Sciences, Queen's Medical Centre, The University of Nottingham, Nottingham, UK.
authors.forename: S
authors.initials: S
authors.lastname: Woods
authors.forename: N N
authors.initials: NN
authors.lastname: Clarke
authors.forename: R
authors.initials: R
authors.lastname: Layfield
authors.forename: K C F
authors.initials: KC
authors.lastname: Fone
mesh_terms: D000818:Animals; D003213:Conditioning, Psychological; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004558:Electric Stimulation; D004644:Emotions; D007211:Indoles / Q000494:pharmacology*; D007858:Learning; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism*; D012601:Scopolamine / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology
chemical_list: C534240:5-chloro-2-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole; C558329:6-chloro-N-(3-(2-(dimethylamino)ethyl)-1H-indol-5-yl)imidazo(2,1-b)thiazole-5-sulfonamide; D007211:Indoles; D011725:Pyridines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; D013844:Thiazoles; D013876:Thiophenes; C097216:serotonin 6 receptor; D016291:Dizocilpine Maleate; D012601:Scopolamine; C117443:SB 271046