Haloperidol-induced alteration in the physiological actions of group I mGlus in the subthalamic nucleus and the substantia nigra pars reticulata.
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.
Marino
M J
MJ
Department of Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA. michael_marino@merck.com
Awad-Granko
H
H
Ciombor
K J
KJ
Conn
P J
PJ
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
D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D006220:Haloperidol