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

► 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.