Effects of the novel 5-HT 6 receptor antagonist RO4368554 in rat models for cognition and sensorimotor gating Rudy Schreiber a, * , Jef Vivian b , Linda Hedley b , Krystine Szczepanski b , Rob L. Secchi b , Marcus Zuzow b , Susanne van Laarhoven b , Jean-Luc Moreau c , James R. Martin c , Ayhan Sik d , Arjan Blokland d a Pharmacology, Discovery Group, Sepracor, Inc., 84 Waterford Drive, Marlborough, 01752-7010, Massachusetts, USA b CNS Neurobehavior, Roche Palo Alto LLC, Palo Alto, California 94304, USA c PRBD-N, Neuroscience Research, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland d Department of Psychology, Brain and Behavior Institute, EURON, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands Received 20 February 2006; received in revised form 21 May 2006; accepted 20 June 2006 Abstract 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 0924-977X/$ - see front matter D 2006 Elsevier B.V. and ECNP. All rights reserved. doi:10.1016/j.euroneuro.2006.06.009 * Corresponding author. Tel.: +1 508 787 4169; fax: +1 508 490 5454. E-mail address: rudy.schreiber@sepracor.com (R. Schreiber). KEYWORDS Acetylcholine; Learning; Memory; Prepulse inhibition; Schizophrenia; Serotonin European Neuropsychopharmacology (2007) 17, 277 — 288 www.elsevier.com/locate/euroneuro