title: Haloperidol-induced alteration in the physiological actions of group I mGlus in the subthalamic nucleus and the substantia nigra pars reticulata.
abstract: Excitatory glutamatergic inputs to the subthalamic nucleus (STN), and subthalamic afferents to the substantia nigra pars reticulata (SNr) are believed to play a key role in the pathophysiology of Parkinson's disease (PD). Previously, we have shown that activation of the group I mGlus in the STN and SNr induces a direct depolarization of the neurons in these nuclei. Surprisingly, although both group I mGlus were present in the STN and SNr, mGlu5 alone mediated the DHPG-induced depolarization of the STN, and mGlu1 alone mediated the DHPG-induced depolarization of the SNr. We now report that both mGlu1 and mGlu5 are coexpressed in the same cells in both of these brain regions, and that both receptors play a role in mediating the DHPG-induced increase in intracellular calcium. Furthermore, we demonstrate that the induction of an acute PD-like state using a 16 h haloperidol treatment produces an alteration in the coupling of the group I receptors, such that post-haloperidol, DHPG-induced depolarizations are mediated by both mGlu1 and mGlu5 in the STN and SNr. Therefore, the pharmacology of the group I mGlu-mediated depolarization depends on the state of the system, and alterations in receptor coupling may be evident in pathological states such as PD.
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA. michael_marino@merck.com
authors.forename: M J
authors.initials: MJ
authors.lastname: Marino
authors.forename: H
authors.initials: H
authors.lastname: Awad-Granko
authors.forename: K J
authors.initials: KJ
authors.lastname: Ciombor
authors.forename: P J
authors.initials: PJ
authors.lastname: Conn
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D006220:Haloperidol / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000032:analysis / Q000502:physiology*; D013378:Substantia Nigra / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D020531:Subthalamic Nucleus / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology
chemical_list: D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D006220:Haloperidol