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

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 (0.1 mg/kg, administered intraperitoneally, i.p., 30 min 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 (1 mg/kg, oral administration, p.o.), GSK-742457 (3 mg/kg, i.p.), CMP X (3 mg/kg, i.p.) and CMP Y (30 mg/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 (1 mg/kg, i.p.) and CMP Y (10 mg/kg, p.o.) with the AChEI donepezil (0.1 mg/kg, p.o.), enhanced memory performance in Wistar rats with deficits induced by scopolamine. Donepezil (0.1 mg/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 (1 mg/kg, p.o.), GSK-742457 (10 mg/kg, p.o.) and CMP Y (30 mg/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.