Excess glutamate-mediated excitation of the substantia nigra pars reticulata (SNpr) is believed to contribute to the akinetic symptoms of Parkinson's disease. Recent reports have shown that single injections of the group III metabotropic glutamate (mGlu) receptor agonist L-SOP into the substantia nigra pars reticulata (SNpr) can reverse reserpine-induced akinesia in the rat (MacInnes et al., 2003), purportedly via activation of group III mGlu autoreceptors on subthalamonigral neurone terminals. The aim of the present study was to investigate whether this behavioural response to L-SOP was sustained following repeated administration.

Under general anaesthesia (Isoflurane, 4%), male Sprague Dawley rats (270-320g) were stereotaxically implanted with 23 gauge guide cannulae above the SNpr. 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 SNpr with L-SOP, 750 nmol (in 2.5 µl Phosphate Buffered Saline, pH 7.4) at 4h intervals for a total of 4 injections (n=6). The number of 360^o contraversive rotations was recorded for 30 min after each injection. For data analysis, the initial response to L-SOP was set at 100% and subsequent responses expressed as a percentage of this initial response. A repeated measures ANOVA with Student Newman-Keul's post hoc test was used to compare the response to each injection of L-SOP.

Following initial injection of L-SOP (750 nmol), rotational behaviour was observed in all animals (66 ± 18 contraversive rotations 30 min^-1; mean ± SEM, n=6). However, a significant reduction in rotations was observed following subsequent exposure to L-SOP (P<0.001; Figure 1). This reduction was maintained for up to 12 h following initial injection.

Figure 1. Rotational behaviour induced by repeated intranigral administration of L-SOP (750 nmol). Values are expressed as a % of initial response at time 0. Data are mean ± S.E.M (n=6). *** P < 0.001, indicates significant difference to time 0.

In conclusion, the reversal of reserpine-induced akinesia seen with L-SOP appears to undergo desensitisation for at least 12h following initial exposure. This is the first time that behavioural desensitisation with a group III mGlu receptor agonist has been reported and the cellular basis for this apparent desensitisation is currently under investigation.

MacInnes et al., (2003). Br. J. Pharmacol., (in press).

This work was funded by a Guy's and St. Thomas' Charitable Foundation Ph.D. Studentship.