Functional interaction between mGlu 5 and NMDA receptors in a rat model of Parkinson's disease.
BACKGROUND
Electrophysiological evidence suggests a synergistic relationship between metabotropic (mGlu) and ionotropic (iGlu) glutamate receptors. The functional consequences of these interactions have not been investigated in neurodegenerative diseases such as in Parkinson's disease.


OBJECTIVE
The goals of this study are as follows: (1) to investigate the effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and dizocilpine (MK-801), antagonists at metabotropic glutamate 5 (mGlu5) and NMDA receptors, respectively, on the akinetic syndrome observed in bilateral 6-OHDA-lesioned rats; (2) to investigate if the effects of MPEP were potentiated by co-treatment with a behaviorally inactive dose of MK-801; and (3) to investigate the effects of L-DOPA alone and in combination with MPEP on the akinetic syndrome observed in 6-OHDA-lesioned rats.


METHODS
The effects of the different treatments (single and co-treatment) administered for 3 weeks were measured in 6-OHDA-lesioned rats trained to release a lever rapidly after a visual stimulus onset in a simple reaction time task.


RESULTS
MPEP 0.75 mg/kg reversed the akinetic deficits produced by striatal dopamine depletion, while MPEP 0.375 mg/kg had no effect. Co-administration with MK-801 0.02 mg/kg, ineffective alone, failed to speed the recovery process of MPEP 0.75 mg/kg but revealed the anti-akinetic action of MPEP 0.375 mg/kg. L-DOPA 3 mg/kg alone had a potent anti-akinetic effect in 6-OHDA lesioned rats, and this effect was not potentiated by a subthreshold MPEP treatment.


CONCLUSIONS
These results support a critical role for mGlu5 receptor blockade in improving parkinsonian symptomatology either as a single treatment or in combination with low concentrations of L-DOPA and demonstrate an interaction between NMDA and mGluR5 in regulating these effects.
Turle-Lorenzo
Nathalie
N
CNRS and Université de Provence, Marseille, France. Marianne.amalric@up.univ-mrs.fr
Breysse
Nathalie
N
Baunez
Christelle
C
Amalric
Marianne
M
D000818:Animals; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004357:Drug Synergism; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000209:etiology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*
C578937:Grm5 protein, rat; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D007980:Levodopa; D016291:Dizocilpine Maleate; C121465:6-methyl-2-(phenylethynyl)pyridine
J Neural Transm Suppl. 1992;38:65-89
1491249
Arch Neurol. 1991 Sep;48(9):977-81
1835370
J Neurosci. 2000 Nov 1;20(21):7871-9
11050106
Exp Neurol. 2002 Sep;177(1):252-64
12429227
J Neural Transm Park Dis Dement Sect. 1994;8(1-2):39-71
7534462
Br J Pharmacol. 1997 Mar;120(6):1007-14
9134210
Neuropharmacology. 1999 Oct;38(10 ):1493-503
10530811
Ann Neurol. 1990 Oct;28(4):539-46
2252365
Eur J Neurosci. 2002 Jan;15(1):120-32
11860512
J Pharmacol Exp Ther. 2003 Jul;306(1):116-23
12660307
Neurosci Biobehav Rev. 1997 Jul;21(4):437-46
9195601
Br J Pharmacol. 2000 Dec;131(7):1429-37
11090117
Neuroscience. 2001;106(3):579-87
11591458
J Neurosci. 2003 Sep 10;23 (23 ):8302-9
12967992
Brain. 1991 Feb;114 ( Pt 1B):513-25
2004254
Eur J Pharmacol. 2000 May 26;397(1):R1-2
10844118
Psychopharmacology (Berl). 2004 Sep;175(3):310-8
15024550
J Neurol Sci. 2000 Dec 1;181(1-2):98-103
11099718
J Pharmacol Exp Ther. 1999 Sep;290(3):1393-408
10454519
Brain Res. 1989 Apr 3;483(2):389-94
2706530
Neuropsychopharmacology. 2004 Jul;29(7):1259-69
15010696
J Neurosci. 2002 Jul 1;22(13):5669-78
12097518
Eur J Neurosci. 1998 Aug;10(8):2694-706
9767399
Eur J Pharmacol. 1990 Jul 17;182(3):611-2
1977595
Neuropharmacology. 2002 Dec;43(8):1199-209
12527469
Neurosci Biobehav Rev. 1997 Jul;21(4):455-68
9195603
Neurobiol Dis. 2002 Jul;10(2):165-86
12127155
Br J Pharmacol. 2001 Feb;132(4):799-806
11181420
Neuropharmacology. 2001 Sep;41(4):413-20
11543761
J Neurosci. 1987 Jul;7(7):2129-34
3112323
Science. 1992 Oct 23;258(5082):597-603
1329206
Eur J Neurosci. 1995 May 1;7(5):972-80
7613632
Exp Neurol. 1998 Jun;151(2):334-42
9628768
Trends Neurosci. 1990 Jul;13(7):281-5
1695404
J Neurosci. 1985 Jun;5(6):1513-21
4009243
Neuropharmacology. 1997 Feb;36(2):265-7
9144665
Annu Rev Pharmacol Toxicol. 1997;37:205-37
9131252
Behav Pharmacol. 1995 Aug;6(5 And 6):508-519
11224358
Psychopharmacology (Berl). 2004 Sep;175(2):179-88
15007533
J Neurosci. 2002 Nov 15;22(22):9679-86
12427823
Psychopharmacology (Berl). 2003 Jan;165(3):245-51
12442203
J Neurosci. 2001 Aug 15;21(16):5925-34
11487615
Annu Rev Biophys Biomol Struct. 1994;23:319-48
7919785