Effects of the novel 5-HT(6) receptor antagonist RO4368554 in rat models for cognition and sensorimotor gating

Serotonin(6) (5-HT6) receptors are almost exclusively located in the central nervous system. High expression in the hippocampus, nucleus accumbens and striatum is consistent with a potential role in cognition and psychosis. The availability of potent, selective and brain-penetrating 5-HT6 antagonists such as 804368554 allows further characterization of the role of the 5-HT6 receptor in these processes. Herein, we tested 804368554 in several cognition tasks, as well as sensorimotor gating tests. Using scopolamine-impaired and unimpaired adult male rats, 804368554 was given in novel object discrimination, social recognition, social discrimination, Morris water maze, passive avoidance and autoshaping procedures. 804368554 reversed the effects of scopolamine in novel object discrimination (active doses in mg/kg, i.p., 3, 10), social recognition (3, 10), social discrimination (1, 3, 10) and passive avoidance (10, 30 i.p. and 100 p.o.) tasks. In unimpaired rats, 804368554 enhanced object discrimination (3, 10; 4-h forgetting interval) and autoshaping learning (3), but was inactive in a water maze task (doses tested: 1-10 mg/kg, i.p.). In tests sensitive to antipsychotics, 804368554 did not reverse sensorimotor gating deficits induced by the psychostimulants dizocilpine and amphetamine (doses tested: 1-30 mg/kg, i.p.) or neonatal lesion of the ventral hippocampus (1-10 mg/kg, i.p.). In conclusion, 804368554 enhanced learning and memory processes in unimpaired and scopolamine-impaired rats, supporting the notion that the cognitive enhancing effects of 5-HT6 receptor antagonists involve modulation of cholinergic neurotransmission