title: Serotonin 5-HT(7) receptor blockade reverses behavioral abnormalities in PACAP-deficient mice and receptor activation promotes neurite extension in primary embryonic hippocampal neurons: therapeutic implications for psychiatric disorders.
abstract: The serotonin 5-HT(7) receptor has been linked to various psychiatric disorders, including schizophrenia, anxiety and depression, and is antagonized by antipsychotics such as risperidone, clozapine and lurasidone. In this study, we examined whether inhibiting the 5-HT(7) receptor could reverse behavioral abnormalities in mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP), an experimental mouse model for psychiatric disorders such as schizophrenia. The selective 5-HT(7) antagonist SB-269970 effectively suppressed abnormal jumping behavior in PACAP-deficient mice. SB-269970 tended to alleviate the higher immobility in the forced swim test in PACAP-deficient mice, although SB-269970 reduced the immobility also in wild-type mice. In addition, we found that mutant mice had impaired performance in the Y-maze test, which was reversed by SB-269970. In the mutant mouse brain, 5-HT(7) protein expression did not differ from wild-type mice. In primary embryonic hippocampal neurons, the 5-HT(7) agonist AS19 increased neurite length and number. Furthermore, SB-269970 significantly inhibited the increase in neurite extension mediated by the 5-HT(1A/7) agonist 8-OH-DPAT. These results indicate that 5-HT(7) receptor blockade ameliorates psychomotor and cognitive deficits in PACAP-deficient mice, providing additional evidence that the 5-HT(7) receptor is a rational target for the treatment of psychiatric disorders.
authors: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Minako
authors: M
authors: Tajiri
authors: Atsuko
authors: A
authors: Hayata-Takano
authors: Kaoru
authors: K
authors: Seiriki
authors: Katsuya
authors: K
authors: Ogata
authors: Keisuke
authors: K
authors: Hazama
authors: Norihito
authors: N
authors: Shintani
authors: Akemichi
authors: A
authors: Baba
authors: Hitoshi
authors: H
authors: Hashimoto
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000037:antagonists & inhibitors / Q000633:toxicity; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002452:Cell Count; D002478:Cells, Cultured / Q000187:drug effects / Q000648:ultrastructure; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005106:Exploratory Behavior / Q000187:drug effects; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology* / Q000196:embryology; D006948:Hyperkinesis / Q000188:drug therapy / Q000503:physiopathology; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016501:Neurites / Q000187:drug effects* / Q000648:ultrastructure; D010636:Phenols / Q000494:pharmacology / Q000627:therapeutic use*; D010807:Physical Endurance / Q000187:drug effects; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000172:deficiency*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011985:Receptors, Serotonin / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012701:Serotonin / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology / Q000633:toxicity; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C505862:AS 19 compound; C495402:Adcyap1 protein, mouse; D014150:Antipsychotic Agents; D009419:Nerve Tissue Proteins; D010636:Phenols; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011720:Pyrazoles; D011985:Receptors, Serotonin; C404922:SB 269970; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; D013764:Tetrahydronaphthalenes; C104425:serotonin 7 receptor; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin