Activation of neurotensin receptor type 1 attenuates locomotor activity

• Published in: Neuropharmacology Vol. 85; pp. 482 - 492
• Main Authors: Vadnie, Chelsea A., Hinton, David J., Choi, Sun, Choi, YuBin, Ruby, Christina L., Oliveros, Alfredo, Prieto, Miguel L., Park, Jun Hyun, Choi, Doo-Sup
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2014
• Subjects: Animals; Benzazepines - pharmacology; Bromocriptine - pharmacology; Central Nervous System Agents - pharmacology; D2R; Dopamine Agonists - pharmacology; Dose-Response Relationship, Drug; Drug Tolerance; Environment; Housing, Animal; Locomotor activity; Male; Mice, Inbred C57BL; Microinjections; Motor Activity - drug effects; Motor Activity - physiology; Muscle Strength - drug effects; Muscle Strength - physiology; Neurotensin; Neurotensin - analogs & derivatives; Neurotensin - pharmacology; NTS1; Nucleus accumbens; Nucleus Accumbens - drug effects; Nucleus Accumbens - physiology; PD149163; Prefrontal Cortex - drug effects; Prefrontal Cortex - physiology; Random Allocation; Receptors, Dopamine - metabolism; Receptors, Neurotensin - agonists; Receptors, Neurotensin - metabolism; Rotarod Performance Test; Nucleus accumbens; NTS1; Neurotensin; D2R; PD149163; Locomotor activity
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2014.05.046

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. •The NTS1 selective agonist PD149163 reduced basal and novelty-induced activity of C57BL/6J mice.•NTS1 activation attenuated dopamine receptor-mediated hyperactivity.•Activation of NTS1 in the nucleus accumbens reduced locomotion, but not in the medial prefrontal cortex.