Activation of group III metabotropic glutamate receptors in selected regions of the basal ganglia alleviates akinesia in the reserpine‐treated rat

Abstract

1 This study examined whether group III metabotropic glutamate (mGlu) receptor agonists injected into the globus pallidus (GP), substantia nigra pars reticulata (SNr) or intracerebroventricularly (i.c.v.) could reverse reserpine-induced akinesia in the rat. 2 Male Sprague -Dawley rats, cannulated above the GP, SNr or third ventricle, were rendered akinetic with reserpine (5 mg kg À1 s.c.). 18 h later, behavioural effects of the group III mGlu receptor3 In reserpine-treated rats, unilateral injection of L-SOP (2000 and 2500 nmol in 2.5 ml) into the GP produced a significant increase in net contraversive rotations compared to vehicle, reaching a maximum of 83721 rotations 120 min À1 (n ¼ 8). Pretreatment with the group III mGlu receptor antagonist methyl-serine-O-phosphate (M-SOP; 250 nmol in 2.5 ml) inhibited the response to L-SOP (2000 nmol) by 77%. 4 Unilateral injection of L-SOP (250-1000 nmol in 2.5 ml) into the SNr of reserpine-treated rats produced a dose-dependent increase in net contraversive rotations, reaching a maximum of 4776 rotations 30 min À1 (n ¼ 6). M-SOP (50 nmol in 2.5 ml) inhibited the response to L-SOP (500 nmol) by 78%. 5 Following i.c.v. injection, L-SOP (2000 -2500 nmol in 2.5 ml) or L-AP4 (0.5 -100 nmol in 2 ml) produced a dose-dependent reversal of akinesia, attaining a maximum of 45717 (n ¼ 8) and 7273 (n ¼ 9) arbitrary locomotor units 30 min À1 , respectively. 6 These studies indicate that injection of group III mGlu receptor agonists into the GP, SNr or cerebral ventricles reverses reserpine-induced akinesia, the mechanism for which remains to be established.

Targeting Group III Metabotropic Glutamate Receptors Produces Complex Behavioral Effects in Rodent Models of Parkinson's Disease

“…Our findings that ACPT-I reverses haloperidol-and 6-OHDAinduced akinesia are in agreement with the antiparkinsonian actions of group III mGluR agonists in pharmacological and lesion models of PD Valenti et al, 2003;MacInnes et al, 2004;Konieczny et al, 2007). Our results extend these findings by demonstrating that dysfunction of glutamate activity at group III mGluRs probably occurs early in the progression of the disease when DA depletion is restricted to the dorsal striatum.…”

“…Similar results were found in reserpine model of PD with L-SOP (L-serine-O-phosphate), another group III agonist (MacInnes et al, 2004). The differential effects produced by ACPT-I in control animals or after haloperidol treatment in the present study may be related to recent evidence demonstrating that dopamine modulates group III mGluR function in the SNr (Wittmann et al, 2002).…”

“…Electrophysiological studies conducted in brain slices elegantly demonstrated that the group III mGluRspecific agonist L-(ϩ)-2-amino-4-phosphonobutyric acid (L-AP4) modulates inhibitory and excitatory transmission in the GP and the SNr (Wittmann et al, 2001;Marino et al, 2003;Matsui and Kita, 2003;Valenti et al, 2003). Group III mGluR agonists have antiparkinsonian actions in reserpine or haloperidoltreated rats Valenti et al, 2003;MacInnes et al, 2004;Konieczny et al, 2007) and in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats by improving forelimb asymmetry and producing contraversive rotation (Kearney et al, 1998;Zhang and Albin, 2000;Valenti et al, 2003). However, the ability of group III mGluR agonists to provide functional relief in the early symptomatic stage of PD remains to be investigated.…”

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

“…Allosteric modulators are particularly helpful because they inhibit or amplify receptor function independently of the concentrations of ambient glutamate and are effective at synapses that are tonically activated by endogenous glutamate. Recent evidence indicates that intracerebroventricular injection of the group III mGlu receptor agonist L-2-amino-4-phosphonobutanoate (L-AP-4) relieves motor symptoms in multiple animal models of parkinsonism and is as efficacious as L-DOPA in decreasing forelimb asymmetry in rats unilaterally lesioned with 6-hydroxydopamine Mac Innes et al, 2004). The action of L-AP-4 is mimicked by N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen1a-carboxamide (PHCCC), which behaves as a selective allosteric potentiator of mGlu4 receptors with no direct agonist activity and no potentiator activity on any other mGlu receptor subtype (Maj et al, 2003;Marino et al, 2003).…”

Activation of Group III Metabotropic Glutamate Receptors Attenuates Rotenone Toxicity on Dopaminergic Neurons through a Microtubule-Dependent Mechanism

“…Because the rest of basal ganglia nuclei are largely intact, rebalancing the activities of the basal ganglia network by selective activation of certain metabotropic glutamate receptors appears to significantly alleviate PD-like symptoms in animal models (Conn et al, 2005). For example, intracerebroventricular injection of L-AP-4 markedly reduces locomotor deficiencies in various animal models of PD (Valenti et al, 2003;Macinnes et al, 2004). The neuroprotective effect of L-AP-4 on DA neurons (this study) may work synergistically with its ability to modulate synaptic transmission in non-DA neurons in basal ganglia (Conn et al, 2005), especially at the early stage of PD before the heavy loss of nigral DA neurons.…”