title: Pharmacological blockade of serotonin 5-HT₇ receptor reverses working memory deficits in rats by normalizing cortical glutamate neurotransmission.
abstract: The role of 5-HT₇ receptor has been demonstrated in various animal models of mood disorders; however its function in cognition remains largely speculative. This study evaluates the effects of SB-269970, a selective 5-HT₇ antagonist, in a translational model of working memory deficit and investigates whether it modulates cortical glutamate and/or dopamine neurotransmission in rats. The effect of SB-269970 was evaluated in the delayed non-matching to position task alone or in combination with MK-801, a non-competitive NMDA receptor antagonist, and, in separate experiments, with scopolamine, a non-selective muscarinic antagonist. SB-269970 (10 mg/kg) significantly reversed the deficits induced by MK-801 (0.1 mg/kg) but augmented the deficit induced by scopolamine (0.06 mg/kg). The ability of SB-269970 to modulate MK-801-induced glutamate and dopamine extracellular levels was separately evaluated using biosensor technology and microdialysis in the prefrontal cortex of freely moving rats. SB-269970 normalized MK-801 -induced glutamate but not dopamine extracellular levels in the prefrontal cortex. Rat plasma and brain concentrations of MK-801 were not affected by co-administration of SB-269970, arguing for a pharmacodynamic rather than a pharmacokinetic mechanism. These results indicate that 5-HT₇ receptor antagonists might reverse cognitive deficits associated with NMDA receptor hypofunction by selectively normalizing glutamatergic neurotransmission.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, L.L.C., San Diego, California, United States of America. Pbonave1@its.jnj.com
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonaventure
authors.forename: Leah
authors.initials: L
authors.lastname: Aluisio
authors.forename: James
authors.initials: J
authors.lastname: Shoblock
authors.forename: Jamin D
authors.initials: JD
authors.lastname: Boggs
authors.forename: Ian C
authors.initials: IC
authors.lastname: Fraser
authors.forename: Brian
authors.initials: B
authors.lastname: Lord
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Lovenberg
authors.forename: Ruggero
authors.initials: R
authors.lastname: Galici
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000493:pharmacokinetics / Q000627:therapeutic use; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000378:metabolism; D008570:Memory, Short-Term / Q000187:drug effects*; D010636:Phenols / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000627:therapeutic use; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D010636:Phenols; D011985:Receptors, Serotonin; C404922:SB 269970; D012702:Serotonin Antagonists; D013449:Sulfonamides; C104425:serotonin 7 receptor; D018698:Glutamic Acid; D016291:Dizocilpine Maleate