We previously reported that acute injection of the group III metabotropic glutamate (mGlu) receptor agonist, L-SOP, into the substantia nigra pars reticulata (SNpr) of rats reverses reserpine-induced akinesia (MacInnes et al., 2004). However, this response appears to desensitise, since repeated injections of L-SOP up to 12 h later produced a negligible response (Broadstock & Duty, 2004). Activation of a second inhibitory G-protein coupled receptor (GABA_B receptor) by acute intranigral administration of baclofen also produces reversal of akinesia (Johnston et al., 2003). The aims of the present study were to examine firstly whether the response to baclofen also desensitised upon repeated administration and secondly whether any reciprocal desensitisation between group III mGlu and GABA_B receptor-mediated responses was apparent.

Under general isoflurane (3%) anaesthesia, male Sprague-Dawley rats (270-320g) were implanted with a cannula above the SNpr. Rats were rendered akinetic 3d later by the injection of reserpine (5 mg kg^-1 s.c.). 18h later, following a 30-min baseline assessment, akinetic rats received a single unilateral injection of either L-SOP (750 nmol in 2.5 µl PBS), baclofen (800ng in 0.5 µl PBS) or equivalent volume of vehicle into the SNpr (all pH 7.4). 4h later a further injection of either L-SOP or baclofen (same doses as above) was performed. The number of 360 o contraversive rotations was recorded for up to 60 min following each injection. To assess for homologous desensitisation, repeat responses to the same agonist were compared using a paired t-test. To assess for heterologous desensitisation, responses to L-SOP and baclofen obtained 4 h after either vehicle or reciprocal agonist injection were compared using an unpaired t-test. In all cases P<0.05 was taken to be significant. Data are expressed as mean ± s.e.m (n=6).

As previously observed, the response to L-SOP was significantly reduced upon second injection (63 ± 18 versus 1.6 ± 1.3 contraversive rotations 30 min^-1 for first and second injections, respectively). The response to L-SOP was also significantly reduced by initial injection with baclofen, attaining 7 ± 3 rotations 30 min^-1 versus 30 ± 6 after initial vehicle injection. Responses to repeat injections of baclofen were significantly reduced with 150 ± 19 contraversive rotations 60 min^-1 at first injection and 35 ± 9 at second. However, the response to baclofen following initial injection with L-SOP (329 ± 29 rotations 60 min^-1) was significantly enhanced when compared to the response to baclofen following initial injection of vehicle (106 ± 4 rotations 60 min^-1).

These data confirm that anti-akinetic responses to baclofen, like L-SOP, reduce upon second agonist exposure indicating possible homologous desensitisation of both group III mGlu and GABA_B receptors. Furthermore, it appears that group III mGlu receptor-mediated responses may also undergo heterologous desensitisation via activation of GABA_B receptors whilst, in stark contrast, GABA_B receptor-mediated responses appear to undergo heterologous potentiation through activation of group III mGlu receptors.

Broadstock, M. & Duty, S. (2004) pA 2online www.pa2online.org/vol1/issue4abst123P.html
Johnston, T. & Duty, S. (2003). Br. J. Pharmacol.,139, 1480-1486.
MacInnes, N. et al. (2004). Br. J. Pharmacol., 141, 15-22.

MB is a Guy’s and St. Thomas’ Charitable Foundation Prize Ph.D. Student.