Reversal of LSOP-mediated locomotor activity in the reserpine-treated rat by the group III metabotropic glutamate receptor antagonist, MSOP, is dose-dependent N. MacInnes & S. Duty. Wolfson Centre for Age Related Diseases, Guy's Campus, King's College London, SE1 1UL.	Print Abstract Search PubMed for: MacInnes N Duty S

Loss of striatal dopaminergic innervation in Parkinson's disease (PD) leads to a downstream increase in glutamate-mediated excitation of the substantia nigra pars reticulata (SNr) that contributes to the generation of symptoms such as akinesia. We have recently reported that microinjection of the group III metabotropic glutamate (mGlu) receptor agonist L-SOP (l-serine-O-phosphate) into the SNr gives remission from reserpine-induced akinesia possibly via activation of group III autoreceptors on subthalamonigral neurone terminals. (MacInnes & Duty, 2003). Here, we examine the ability of the group III mGlu receptor antagonist, MSOP, to antagonise this anti-akinetic response of LSOP.

Under general anaesthesia (2.5%halothane), male Sprague Dawley rats (270-300g) were stereotaxically implanted with a 23 gauge guide cannula above the SNr. Animals were rendered akinetic 3d later by the injection of reserpine (5 mg kg^-1 s.c.). 18h later, following a 30-min baseline assessment, animals were unilaterally injected into the SNr with MSOP (50, 250 or 500 nmol in 2.5 µl Phosphate Buffered Saline, PBS; pH 7.4) or vehicle (PBS); n=6-8 per treatment. 30 min later a fixed concentration (500 nmol in 2.5 µl PBS; pH 7.4) of LSOP was administered. The number of full contraversive rotations was recorded throughout the dosing period and for a further 30 min post LSOP administration. Data were recorded in 10-min time bins and a 2-way mixed design ANOVA with Dunnett's post hoc test was used to assess the effects of MSOP alone (0-30 min) and the effect of MSOP on subsequent LSOP challenge (30-60 min).

In comparison to vehicle, 500 nmol MSOP induced significant levels of motor activity over the first 30 min (Figure 1a), with a significant elevation apparent in all three 10-min bins (all, P<0.01). In contrast, only the lowest dose of MSOP (50 nmol) antagonised LSOP-induced locomotor activity between 30 and 60 min (Figure 1b), with this reduction significant only in the first 10-min period after LSOP administration (P<0.05).

Figure 1. (a) Locomotor activity induced by intranigral injection of MSOP or vehicle and (b) effect of MSOP or vehicle on subsequent LSOP (500 nmol)-induced motor activity. Values are mean ± S.E.M. *P<0.05, **P<0.001, indicates significant difference to vehicle-treated group.

In conclusion, the inhibition of LSOP-mediated reversal of akinesia by the lowest dose of MSOP confirms involvement of group III mGlu receptors in mediating this response. That the highest dose of MSOP gave rise to remission from akinesia itself indicates that, in this behavioural model, MSOP may act as a partial agonist at high doses.

MacInnes N and Duty S. (2003). Br. J. Pharmacol., 138, 226P.

This work was funded by Merck Sharp & Dohme.