Effects of SB-269970, a 5-HT7 receptor antagonist, in mouse models predictive of antipsychotic-like activity.
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.
Galici
Ruggero
R
Johnson & Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA. rgalici@prdus.jnj.com
Boggs
Jamin D
JD
Miller
Kirsten L
KL
Bonaventure
Pascal
P
Atack
John R
JR
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001143:Arousal / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005973:Glutamine / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D010636:Phenols / Q000494:pharmacology*; D011618:Psychotic Disorders / Q000523:psychology*; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000235:genetics; D013216:Reflex, Startle / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects
D014150:Antipsychotic Agents; D010636:Phenols; D011985:Receptors, Serotonin; C404922:SB 269970; D013449:Sulfonamides; C104425:serotonin 7 receptor; D005973:Glutamine; D007649:Ketamine; D000661:Amphetamine; D004298:Dopamine