The group II metabotropic glutamate receptor agonist, DCG‐IV, alleviates akinesia following intranigral or intraventricular administration in the reserpine‐treated rat

Abstract

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 71 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 ml) produced a dose-dependent increase in net contraversive rotations (n=6 ± 8 animals per dose), reaching a maximum of 395+51 rotations 60 min 71 after 0.75 nmol. The eects 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)-a-ethylglutamic acid (EGLU; 100 nmol in 0.2 ml; n=6). 4 Following intraventricular injection, DCG-IV (0.125 ± 1.5 nmol in 2 ml) produced a dosedependent increase in bilateral locomotor activity (n=6 ± 7 animals per dose), reaching a maximum of 180+21 locomotor units 30 min 71 after 0.5 nmol. Pre-treatment with EGLU (200 nmol in 2 ml) inhibited the eects 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 bene®t of systemically-active group II mGlu receptor agonists in PD.

Characterisation of an mGlu8 receptor-selective agonist and antagonist in the lateral and medial perforant path inputs to the dentate gyrus

“…For instance, a recent study investigating the anti-parkinsonian potential of group III mGlu receptors found that DCPG could significantly reverse akinesia in reserpine-treated rats, but that this effect could not be blocked by a broad spectrum group III mGlu receptor antagonist (Broadstock et al, 2011). Given that group II mGlu receptor agonists have also been shown to alleviate akinesia in the same model of Parkinson's disease (Dawson et al, 2000), it therefore seems possible that the DCPG effects observed in the former study were mediated by mGlu2 receptors.…”

Simultaneous Blockade of Adenosine A2A and Metabotropic Glutamate mGlu5 Receptors Increase their Efficacy in Reversing Parkinsonian Deficits in Rats

“…Systemic or intrastriatal administration of group I mGluR (subtypes 1 and 5) antagonists reversed catalepsy induced by a DA receptor blockade or DA depletion (Konieczny et al, 1998;Dawson et al, 2000;Ossowska et al, 2001). In unilateral and bilateral 6-OHDA models of PD, a chronic but not acute treatment with MPEP induced ipsilateral circling behavior and produced a full recovery of akinesia in the RT task (Spooren et al, 2000;Breysse et al, 2002).…”

Pharmacological Activation of mGlu4 Metabotropic Glutamate Receptors Reduces Nigrostriatal Degeneration in Mice Treated with 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine

“…Pharmacological activation of mGlu2/3 receptors is also protective, whereas mGlu2/3 receptor blockade amplifies MPTP neurotoxicity (Matarredona et al, 2001;Battaglia et al, 2003). These findings are interesting because mGlu5 receptor antagonists and mGlu2/3 receptor agonists improve motor symptoms in experimental animal models of parkinsonism (Konieczny et al, 1998;Dawson et al, 2000;Kronthaler and Schmidt, 2000;Wolfarth et al, 2000;Lorenc-Koci et al, 2001;Breysse et al, 2002). We decided to examine the role of mGlu4 receptors in MPTP toxicity because these receptors are one the most promising targets for symptomatic drugs in experimental parkinsonism.…”