title: Melanin-concentrating hormone is necessary for olanzapine-inhibited locomotor activity in male mice.
abstract: Olanzapine (OLZ), an atypical antipsychotic, can be effective in treating patients with restricting type anorexia nervosa who exercise excessively. Clinical improvements include weight gain and reduced pathological hyperactivity. However the neuronal populations and mechanisms underlying OLZ actions are not known. We studied the effects of OLZ on hyperactivity using male mice lacking the hypothalamic neuropeptide melanin-concentrating hormone (MCHKO) that are lean and hyperactive. We compared the in vivo effects of systemic or intra-accumbens nucleus (Acb) OLZ administration on locomotor activity in WT and MCHKO littermates. Acute systemic OLZ treatment in WT mice significantly reduced locomotor activity, an effect that is substantially attenuated in MCHKO mice. Furthermore, OLZ infusion directly into the Acb of WT mice reduced locomotor activity, but not in MCHKO mice. To identify contributing neuronal mechanisms, we assessed the effect of OLZ treatment on Acb synaptic transmission ex vivo and in vitro. Intraperitoneal OLZ treatment reduced Acb GABAergic activity in WT but not MCHKO neurons. This effect was also seen in vitro by applying OLZ to acute brain slices. OLZ reduced the frequency and amplitude of GABAergic activity that was more robust in WT than MCHKO Acb. These findings indicate that OLZ reduced Acb GABAergic transmission and that MCH is necessary for the hypolocomotor effects of OLZ.
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Melissa J S
authors.initials: MJ
authors.lastname: Chee
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Douris
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Avery B
authors.initials: AB
authors.lastname: Forrow
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Monnard
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Shuangyu
authors.initials: S
authors.lastname: Lu
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Flaherty
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Adams
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. Electronic address: emaratos@bidmc.harvard.edu.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Maratos-Flier
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D002491:Central Nervous System Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007028:Hypothalamic Hormones / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008543:Melanins / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000502:physiology; D000077152:Olanzapine; D018408:Patch-Clamp Techniques; D010907:Pituitary Hormones / Q000235:genetics / Q000378:metabolism*; D012420:Running / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D002491:Central Nervous System Agents; D007028:Hypothalamic Hormones; D008543:Melanins; D010907:Pituitary Hormones; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid; C019463:melanin-concentrating hormone; D000077152:Olanzapine
keywords: Accumbens nucleus; Anorexia; Antipsychotic; Electrophysiology; Locomotion; MCH