Effects of the novel 5-HT(6) receptor antagonist RO4368554 in rat models for cognition and sensorimotor gating.
Serotonin(6) (5-HT(6)) 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-HT(6) antagonists such as RO4368554 allows further characterization of the role of the 5-HT(6) receptor in these processes. Herein, we tested RO4368554 in several cognition tasks, as well as sensorimotor gating tests. Using scopolamine-impaired and unimpaired adult male rats, RO4368554 was given in novel object discrimination, social recognition, social discrimination, Morris water maze, passive avoidance and autoshaping procedures. RO4368554 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, RO4368554 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, RO4368554 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, RO4368554 enhanced learning and memory processes in unimpaired and scopolamine-impaired rats, supporting the notion that the cognitive enhancing effects of 5-HT(6) receptor antagonists involve modulation of cholinergic neurotransmission.
Schreiber
Rudy
R
Pharmacology, Discovery Group, Sepracor, Inc., 84 Waterford Drive, Marlborough, Massachusetts 01752-7010, USA. rudy.schreiber@sepracor.com
Vivian
Jef
J
Hedley
Linda
L
Szczepanski
Krystine
K
Secchi
Rob L
RL
Zuzow
Marcus
M
van Laarhoven
Susanne
S
Moreau
Jean-Luc
JL
Martin
James R
JR
Sik
Ayhan
A
Blokland
Arjan
A
D000161:Acoustic Stimulation; D000704:Analysis of Variance; D000818:Animals; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D020233:Gait Disorders, Neurologic / Q000139:chemically induced / Q000188:drug therapy*; D006624:Hippocampus / Q000187:drug effects / Q000293:injuries / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use*; D007266:Inhibition, Psychological; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009483:Neuropsychological Tests; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D013216:Reflex, Startle / Q000187:drug effects; D012601:Scopolamine; D012702:Serotonin Antagonists / Q000494:pharmacology* / Q000627:therapeutic use*; D012919:Social Behavior
D007211:Indoles; D010879:Piperazines; C507242:Ro4368554; D012702:Serotonin Antagonists; D012601:Scopolamine