title: Antipsychotic-like effects of a neurotensin receptor type 1 agonist.
abstract: Although neurotensin (NT) analogs are known to produce antipsychotic-like effects, the therapeutic possibility of a brain penetrant NTS1 agonist in treating psychiatric disorders has not been well studied. Here, we examined whether PD149163, a brain-penetrant NTS1-specific agonist, displays antipsychotic-like effects in C57BL/6J mice by investigating the effect of PD149163 on amphetamine-mediated hyperactivity and amphetamine-induced disruption of prepulse inhibition. In addition, we assessed the effect of PD149163 on glycogen synthase kinase-3 (GSK-3) activity, a downstream molecular target of antipsychotics and mood stabilizers, using phospho-specific antibodies. PD149163 (0.1 and 0.5mg/kg) inhibited amphetamine-induced hyperactivity in mice, indicating that NTS1 activation inhibits psychomotor agitation. PD149163 (0.5mg/kg) also increased prepulse inhibition, suggesting that NTS1 activation reduces prepulse inhibition deficits which often co-occur with psychosis in humans. Interestingly, PD149163 increased the inhibitory serine phosphorylation on both GSK-3α and GSK-3β in a dose- and time-dependent manner in the nucleus accumbens and medial prefrontal cortex of the mice. Moreover, PD149163 inhibited GSK-3 activity in the nucleus accumbens and medial prefrontal cortex in the presence of amphetamine. Thus, like most current antipsychotics and mood stabilizers, PD149163 inhibited GSK-3 activity in cortico-striatal circuitry. Together, our findings indicate that PD149163 may be a novel antipsychotic.
authors.affiliation: Neurobiology of Disease Program, Mayo Graduate School, Rochester, MN, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Chelsea A
authors.initials: CA
authors.lastname: Vadnie
authors.affiliation: Neurobiology of Disease Program, Mayo Graduate School, Rochester, MN, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ayers-Ringler
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Oliveros
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Osama A
authors.initials: OA
authors.lastname: Abulseoud
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Sun
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Mario J
authors.initials: MJ
authors.lastname: Hitschfeld
authors.affiliation: Neurobiology of Disease Program, Mayo Graduate School, Rochester, MN, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA; Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, USA. Electronic address: choids@mayo.edu.
authors.forename: Doo-Sup
authors.initials: DS
authors.lastname: Choi
mesh_terms: D000661:Amphetamine / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009496:Neurotensin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D065808:Prepulse Inhibition / Q000187:drug effects; D011595:Psychomotor Agitation / Q000188:drug therapy* / Q000209:etiology; D012694:Serine / Q000378:metabolism; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; C117269:PD 149163; D009496:Neurotensin; D012694:Serine; D000661:Amphetamine; D038362:Glycogen Synthase Kinase 3
keywords: Amphetamine; Glycogen synthase kinase 3; Locomotion; Neurotensin type 1 receptor; Prepulse inhibition