Issn Print: 0955-8810

Publication Date: 2005/09/01


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B12 METABOTROPIC GLUTAMATE RECEPTORS AS POTENTIAL TARGETS OF ANTIPARKINSONIAN THERAPY

K. Ossowska; J. Konieczny; J. Wardas; M. Pietraszek; S. Wolfarth; A. Pilc

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Author Information: Department of Neuro-Psychopharmacology, Institute of Pharmacology, Krakow, Poland

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Excerpt

Data indicate that inhibition of glutamatergic transmission may be important in alleviation of parkinsonian symptoms. However, the use of antagonists of ionotropic glutamate receptors in humans is limited because of their serious side-effects. In contrast, ligands of metabotropic glutamate receptors (mGluRs) seem to be safer and, therefore, more promising. Therefore, the aim of the present study was to search for brain targets of putative antiparkinsonian-like effects of mGluR ligands. In order to inhibit glutamatergic transmission, we blocked group I mGluRs (mGluR1 and mGluR5), or activated groups II (mGluR2/3) and III (mGluR4/7/8).
We found that either systemic or intrastriatal administration of group I mGluR antagonists (mGluR5: MPEP, MTEP; mGluR1: AIDA) inhibited parkinsonian-like symptoms (catalepsy, muscle rigidity) in rats. MPEP administered systemically and antagonists of mGluR1 (AIDA, CPCCOEt, LY37385) injected intrastriatally also reversed haloperidol-increased proenkephalin (PENK) mRNA expression in the striopallidal pathway. Similarly, ACPT-1 – an agonist of group III mGluRs (with a preference for mGluR4) – administered into the striatum, globus pallidus or substantia nigra inhibited the catalepsy induced by haloperidol. In contrast, agonists of group II (2R,4R-APDC, DCG-IV) administered intrastriatally or into the lateral ventricle reduced neither PENK expression nor the above-mentioned parkinsonian-like symptoms. Moreover, a mixed mGluR8 agonist/AMPA antagonist, (R,S)-3,4-DCPG, evoked catalepsy and enhanced both the catalepsy and PENK expression induced by haloperidol.
The present results seem to indicate that antagonists of group I mGluRs or preferential agonists of mGluR4 may possess antiparkinsonian properties, and point at the striopallidal pathway as a potential target of therapeutic intervention.
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