ORIGINAL ARTICLESEffects of SB-269970, a 5-HT7 receptor antagonist, in mouse models predictive of antipsychotic-like activityGalici, Ruggero; Boggs, Jamin D.; Miller, Kirsten L.; Bonaventure, Pascal; Atack, John R. Author Information Johnson & Johnson Pharmaceutical Research and Development, LLC, San Diego, California, USA Correspondence to Dr Ruggero Galici, Johnson & Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA E-mail: [email protected] Received 30 August 2007 Accepted as revised 28 December 2007 Behavioural Pharmacology: March 2008 - Volume 19 - Issue 2 - p 153-159 doi: 10.1097/FBP.0b013e3282f62d8c Buy Metrics Abstract 5-HT7 receptors have been linked to a number of psychiatric disorders including anxiety and depression. The localization of 5-HT7 receptors in the thalamus, a key sensory processing center, and the high affinity of many atypical antipsychotic compounds for these receptors have led to the speculation of the utility of 5-HT7 antagonists in schizophrenia. The goal of these studies was to examine the effects of pharmacologic blockade and genetic ablation of 5-HT7 receptors in animal models predictive of antipsychotic-like activity. We evaluated the effects of SB-269970, a selective 5-HT7 receptor antagonist, on amphetamine and ketamine-induced hyperactivity and prepulse inhibition (PPI) deficits. In addition, sensorimotor gating function and locomotor activity were evaluated in 5-HT7 knockout mice. Locomotor activity was measured for up to 180 min using an automated infrared photobeam system, and PPI was evaluated in startle chambers. SB-269970 (3, 10 and 30 mg/kg, intraperitoneally) significantly blocked amphetamine [3 mg/kg, subcutaneously (s.c.)] and ketamine (30 mg/kg, s.c.)-induced hyperactivity and reversed amphetamine (10 mg/kg, s.c.)-induced but not ketamine (30 mg/kg, s.c.)-induced PPI deficits, without changing spontaneous locomotor activity and startle amplitude. The largest dose of SB-269970 did not block the effects of amphetamine in 5-HT7 knockout mice. Collectively, these results indicate that blockade of 5-HT7 receptors partially modulates glutamatergic and dopaminergic function and could be clinically useful for the treatment of positive symptoms of schizophrenia. © 2008 Lippincott Williams & Wilkins, Inc.