The group II metabotropic glutamate receptor agonist, DCG-IV, alleviates akinesia following intranigral or intraventricular administration in the reserpine-treated rat.
1. This study examined whether activation of group II metabotropic glutamate (mGlu) receptors in the substantia nigra pars reticulata (SNr) could reverse akinesia in a rodent model of Parkinson's disease (PD). 2. Male Sprague Dawley rats, stereotaxically cannulated above either the SNr or third ventricle, were rendered akinetic by injection of reserpine (5 mg kg-1 s.c.). Eighteen hours later, the rotational behaviour induced by unilateral injection of the group II mGlu receptor agonist, (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV), was examined. 3. Following intranigral injection, DCG-IV (0.125-0.75 nmol in 0.1 microliter) produced a dose-dependent increase in net contraversive rotations (n = 6-8 animals per dose), reaching a maximum of 395 +/- 51 rotations 60 min-1 after 0.75 nmol. The effects of DCG-IV (0.5 nmol) were inhibited by 63.0 +/- 9.0% following 30 min pre-treatment with the group II mGlu receptor antagonist, (2S)-alpha-ethylglutamic acid (EGLU; 100 nmol in 0.2 microliter; n = 6). 4. Following intraventricular injection, DCG-IV (0.125-1.5 nmol in 2 microliters) produced a dose-dependent increase in bilateral locomotor activity (n = 6-7 animals per dose), reaching a maximum of 180 +/- 21 locomotor units 30 min-1 after 0.5 nmol. Pre-treatment with EGLU (200 nmol in 2 microliters) inhibited the effects of DCG-IV (0.5 nmol) by 68.2 +/- 12.3% (n = 5). 5. These data show that activation of group II mGlu receptors in the SNr provides relief of akinesia in the reserpinized rat model of PD. The reversal seen following intraventricular administration supports the likely therapeutic benefit of systemically-active group II mGlu receptor agonists in PD.
Dawson
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L
Neurodegenerative Disease Research Group, Wolfson Centre for Age-Related Diseases, GKT School of Biomedical Sciences, King's College London.
Chadha
A
A
Megalou
M
M
Duty
S
S
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity; D003521:Cyclopropanes / Q000494:pharmacology*; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007267:Injections; D007276:Injections, Intraventricular; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000037:antagonists & inhibitors; D012110:Reserpine / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity; D013378:Substantia Nigra
D000927:Anticonvulsants; D014150:Antipsychotic Agents; D003521:Cyclopropanes; D018094:Receptors, Metabotropic Glutamate; C082313:2-(2,3-dicarboxycyclopropyl)glycine; D012110:Reserpine; D005998:Glycine