Intrapallidal metabotropic glutamate receptor activation in a rat model of Parkinson's disease: behavioral and histological analyses

Brain Res. 2008 Apr 8:1203:189-96. doi: 10.1016/j.brainres.2008.01.051. Epub 2008 Jan 30.

Abstract

Metabotropic glutamate receptors (mGluRs) have been recently implicated as robust therapeutic targets for Parkinson's disease (PD). Here, we explored how activation of mGluRs in globus pallidus (GP) affected the amphetamine-induced rotational behavior in the unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of PD. The amphetamine-induced rotations were completely suppressed by the ipsilateral intrapallidal injection of the non-selective mGluR agonist, 1-aminocyclopentane-1S,3R-dicarboxylic acid (ACPD) and the selective group I mGluR agonist, (R,S)-3,5-dihydroxyphenylglycine (DHPG), but not the selective group III mGluR agonist, l-2-amino-4-phosphonobutyric acid (l-AP4). The suppressive effects were detected at 2, 4, 6, 8, and 12 h after ACPD injection, but returned to the control level at 24 h. A remarkable c-fos expression was found in the lesioned side of GP, subthalamic nucleus (STN), and substantia nigra pars reticulata (SNr) of rats that received the ACPD or DHPG injection, compared to rats treated with L-AP-4 or phosphate buffer-injection. The results indicate that the blockade of amphetamine-induced rotations might be at least partially mediated by group I mGluR activation. This study advances the use of selective group I mGluRs directed toward the GP for PD treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Agents / toxicity
  • Analysis of Variance
  • Animals
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology*
  • Dioxolanes / pharmacology
  • Disease Models, Animal
  • Drug Interactions
  • Excitatory Amino Acid Antagonists / pharmacology
  • Female
  • Globus Pallidus / metabolism*
  • Methoxyhydroxyphenylglycol / analogs & derivatives
  • Methoxyhydroxyphenylglycol / pharmacology
  • Motor Activity / drug effects
  • Oxidopamine / toxicity
  • Parkinson Disease / etiology
  • Parkinson Disease / pathology*
  • Parkinson Disease / physiopathology*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Purines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Metabotropic Glutamate / metabolism*
  • Substantia Nigra / drug effects
  • Time Factors
  • Tyrosine 3-Monooxygenase / metabolism

Substances

  • Adrenergic Agents
  • Dioxolanes
  • Excitatory Amino Acid Antagonists
  • Proto-Oncogene Proteins c-fos
  • Purines
  • Receptors, Metabotropic Glutamate
  • 4-(2-amino-6-chloro-9H-purin-9-yl)-1,3-dioxolane-2-methanol
  • Methoxyhydroxyphenylglycol
  • Oxidopamine
  • Tyrosine 3-Monooxygenase
  • 3,4-dihydroxyphenylglycol