title: Activation of neurotensin receptor type 1 attenuates locomotor activity.
abstract: Intracerebroventricular administration of neurotensin (NT) suppresses locomotor activity. However, the brain regions that mediate the locomotor depressant effect of NT and receptor subtype-specific mechanisms involved are unclear. Using a brain-penetrating, selective NT receptor type 1 (NTS1) agonist PD149163, we investigated the effect of systemic and brain region-specific NTS1 activation on locomotor activity. Systemic administration of PD149163 attenuated the locomotor activity of C57BL/6J mice both in a novel environment and in their homecage. However, mice developed tolerance to the hypolocomotor effect of PD149163 (0.1 mg/kg, i.p.). Since NTS1 is known to modulate dopaminergic signaling, we examined whether PD149163 blocks dopamine receptor-mediated hyperactivity. Pretreatment with PD149163 (0.1 or 0.05 mg/kg, i.p.) inhibited D2R agonist bromocriptine (8 mg/kg, i.p.)-mediated hyperactivity. D1R agonist SKF-81297 (8 mg/kg, i.p.)-induced hyperlocomotion was only inhibited by 0.1 mg/kg of PD149163. Since the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) have been implicated in the behavioral effects of NT, we examined whether microinjection of PD149163 into these regions reduces locomotion. Microinjection of PD149163 (2 pmol) into the NAc, but not the mPFC suppressed locomotor activity. In summary, our results indicate that systemic and intra-NAc activation of NTS1 is sufficient to reduce locomotion and NTS1 activation inhibits D2R-mediated hyperactivity. Our study will be helpful to identify pharmacological factors and a possible therapeutic window for NTS1-targeted therapies for movement disorders.
authors.affiliation: Neurobiology of Disease Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Chelsea A
authors.initials: CA
authors.lastname: Vadnie
authors.affiliation: Neurobiology of Disease Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hinton
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Sun
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: YuBin
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Ruby
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Oliveros
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Universidad de los Andes, Facultad de Medicina, Departamento de Psiquiatría, Santiago, Chile.
authors.forename: Miguel L
authors.initials: ML
authors.lastname: Prieto
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Jun Hyun
authors.initials: JH
authors.lastname: Park
authors.affiliation: Neurobiology of Disease Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. Electronic address: choids@mayo.edu.
authors.forename: Doo-Sup
authors.initials: DS
authors.lastname: Choi
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001971:Bromocriptine / Q000494:pharmacology; D002491:Central Nervous System Agents / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004777:Environment; D006799:Housing, Animal; D008297:Male; D008810:Mice, Inbred C57BL; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D053580:Muscle Strength / Q000187:drug effects / Q000502:physiology; D009496:Neurotensin / Q000031:analogs & derivatives* / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000502:physiology; D011897:Random Allocation; D011954:Receptors, Dopamine / Q000378:metabolism; D018028:Receptors, Neurotensin / Q000819:agonists* / Q000378:metabolism; D045442:Rotarod Performance Test
chemical_list: D001552:Benzazepines; D002491:Central Nervous System Agents; D018491:Dopamine Agonists; C117269:PD 149163; D011954:Receptors, Dopamine; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; D009496:Neurotensin; D001971:Bromocriptine; C067113:SK&F 81297
keywords: D2R; Locomotor activity; NTS1; Neurotensin; Nucleus accumbens; PD149163