title: Lu AF21934, a positive allosteric modulator of mGlu4 receptors, reduces the harmaline-induced hyperactivity but not tremor in rats.
abstract: Harmaline induces tremor in animals resembling essential tremor which has been suggested to result from activation of the glutamatergic olivo-cerebellar projection. The aim of the present study was to examine the effects of systemic administration of Lu AF21934, a brain-penetrating positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu4), on the harmaline-induced tremor and other forms of motor activity in rats using fully automated Force Plate Actimeters. The influence of harmaline on the mGlu4 mRNA expression in the cerebellum and inferior olive was analysed by in situ hybridization. Harmaline at a dose of 15 mg/kg (ip) triggered tremor which was manifested by an increase in the power within 9-15 Hz band and in the tremor index (a difference in power between bands 9-15 Hz and 0-8 Hz). Harmaline induced a biphasic effect on mobility, initially inhibiting the exploratory locomotor activity of rats (0-30 min after administration), followed by an increase in their basic activity. Lu AF21934 (0.5-5 mg/kg sc) did not influence tremor but at doses of 0.5 and 2.5 mg/kg reversed harmaline-induced hyperactivity. MGlu4 mRNA expression was high in the cerebellar cortex and low in the inferior olive. Repeated harmaline (15 mg/kg ip once a day for 5 days] decreased mGlu4 mRNA in the cerebellum and inferior olive. The present study indicates that the mGlu4 stimulation counteracts hyperactivity induced by harmaline which suggests the involvement of cerebellar glutamatergic transmission in this process. In contrast, neuronal mechanisms involved in tremor seem to be insensitive to the stimulation of mGlu4.
authors.affiliation: Department of Neuro-Psychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343 Kraków, Poland. Electronic address: ossowska@if-pan.krakow.pl.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Ossowska
authors.affiliation: Department of Neuro-Psychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343 Kraków, Poland.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Wardas
authors.affiliation: Department of Neuro-Psychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343 Kraków, Poland.
authors.forename: Klemencja
authors.initials: K
authors.lastname: Berghauzen-Maciejewska
authors.affiliation: Department of Neuro-Psychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343 Kraków, Poland.
authors.forename: Urszula
authors.initials: U
authors.lastname: Głowacka
authors.affiliation: Department of Neuro-Psychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343 Kraków, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kuter
authors.affiliation: Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, 12, Smętna St., 31-343 Kraków, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Pilc
authors.affiliation: Discovery Chemistry & DMPK, Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, USA.
authors.forename: Stevin H
authors.initials: SH
authors.lastname: Zorn
authors.affiliation: Discovery Chemistry & DMPK, Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, USA.
authors.forename: Dario
authors.initials: D
authors.lastname: Doller
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002531:Cerebellum / Q000187:drug effects; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D006246:Harmaline; D006948:Hyperkinesis / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism*; D014202:Tremor / Q000139:chemically induced / Q000378:metabolism*
chemical_list: D000813:Anilides; D000697:Central Nervous System Stimulants; D003509:Cyclohexanecarboxylic Acids; C581971:N1-(3,4-dichlorophenyl)-cyclohexane-1,2-dicarboxamide; D018094:Receptors, Metabotropic Glutamate; D006246:Harmaline; C108823:metabotropic glutamate receptor 4
keywords: Cerebellum; Harmaline; Hyperactivation; Inferior olive; Metabotropic glutamate receptor 4; Tremor