Two novel 5-HT6 receptor antagonists ameliorate scopolamine-induced memory deficits in the object recognition and object location tasks in Wistar rats

• Published in: Neurobiology of learning and memory Vol. 96; no. 2; pp. 392 - 402
• Main Authors: de Bruin, N.M.W.J., Prickaerts, J., van Loevezijn, A., Venhorst, J., de Groote, L., Houba, P., Reneerkens, O., Akkerman, S., Kruse, C.G.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01-09-2011; Elsevier; Elsevier BV
• Subjects: 5-HT6 antagonist; Alzheimer's disease; Animal cognition; Animals; Behavioral psychophysiology; Biological and medical sciences; Cholinesterase Inhibitors - pharmacology; Cholinesterase Inhibitors - therapeutic use; Donepezil; Exploratory Behavior - drug effects; Fundamental and applied biological sciences. Psychology; GSK-742457; Guanidines - pharmacology; Guanidines - therapeutic use; Indans - pharmacology; Indans - therapeutic use; Male; Maze Learning - drug effects; Medical sciences; Memory; Memory Disorders - chemically induced; Memory Disorders - drug therapy; Neurobiology; Neuropharmacology; Neurotransmitters; Nootropic Agents - pharmacology; Nootropic Agents - therapeutic use; Object location task (OLT); Object recognition task (ORT); Pharmacology; Pharmacology. Drug treatments; Piperidines - pharmacology; Piperidines - therapeutic use; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Psychopharmacology; Rats; Rats, Wistar; Recognition (Psychology) - drug effects; Rodents; Scopolamine; Scopolamine Hydrobromide - pharmacology; Serotonin Antagonists - pharmacology; Serotonin Antagonists - therapeutic use; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Wistar rats; Object location task (OLT); Wistar rats; GSK-742457; Scopolamine; Object recognition task (ORT); Donepezil; 5-HT6 antagonist; Memory disorder; Cognitive disorder; Rat; Psychotropic; 5-HT6 serotonin receptor; Esterases; Acetylcholinesterase; Alkaloid; Piperidine derivatives; Anticholinesterase agent; Antagonist; Object location; Hyoscine; Enzyme; Rodentia; Enzyme inhibitor; Antialzheimer agent; Carboxylic ester hydrolases; Anticholinergic agent; Vertebrata; Mammalia; Animal; Nootropic agent; Hydrolases; 5-HT; Recognition
• ISSN: 1074-7427; 1095-9564
• DOI: 10.1016/j.nlm.2011.06.015

► CMP X and CMP Y are two novel and highly selective 5-HT6 receptor antagonists. ► CMP X and CMP Y improved scopolamine-induced deficits in tests for episodic memory. ► Donepezil and reference 5-HT6 antagonist GSK-742457 also improved performance. ► Co-adm. of CMP X, CMP Y with donepezil resulted in additive cogn. enhancing effects. ► 5-HT6 antagonists could have potential as adjunctive therapy to donepezil.
The 5-hydroxytryptamine6 (5-HT6) receptor has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the novel, selective 5-HT6 antagonists compound (CMP) X and CMP Y and the reference 5-HT6 antagonist GSK-742457 could ameliorate impairments in episodic memory in 3-months-old male Wistar rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept®, approved for symptomatic treatment of Alzheimer’s disease, AD) was used as a positive reference compound. First, effects of the 5-HT6 antagonists CMP X, CMP Y and GSK-742457 were investigated on object recognition task (ORT) performance in rats treated with the muscarinic antagonist scopolamine (0.1mg/kg, administered intraperitoneally, i.p., 30min before trial 1). Second, effects of the combination of suboptimal doses of 5-HT6 antagonists CMP X and CMP Y with the AChEI donepezil were studied, to determine whether the 5-HT6 antagonists show additive synergism with donepezil in the ORT. Finally, effects of CMP Y, GSK-742457 and donepezil were investigated on object location task (OLT) performance in rats treated with scopolamine.
Donepezil (1mg/kg, oral administration, p.o.), GSK-742457 (3mg/kg, i.p.), CMP X (3mg/kg, i.p.) and CMP Y (30mg/kg, p.o.), all ameliorated the scopolamine-induced deficits in object recognition. In the ORT, we have found that combined administration of subthreshold doses of CMP X (1mg/kg, i.p.) and CMP Y (10mg/kg, p.o.) with the AChEI donepezil (0.1mg/kg, p.o.), enhanced memory performance in Wistar rats with deficits induced by scopolamine. Donepezil (0.1mg/kg, p.o.) alone had no discernable effects on performance. This suggests additive synergistic effects of the 5-HT6 antagonists (CMP X and CMP Y) with donepezil on cognitive impairment. Finally, donepezil (1mg/kg, p.o.), GSK-742457 (10mg/kg, p.o.) and CMP Y (30mg/kg, p.o.) also reduced scopolamine-induced deficits in the OLT.
In conclusion, the 5-HT6 antagonists were found to clearly improve episodic memory deficits induced by scopolamine. In addition, co-administration of the 5-HT6 receptor antagonists CMP X and CMP Y with the AChEI donepezil to cognitively impaired rats also resulted in potentially additive enhancing effects on cognition. This suggests that these compounds could have potential as monotherapy, but also as adjunctive therapy in patients with AD treated with common treatments such as donepezil.