| pA2 online © Copyright 2004 The British Pharmacological Society |
120P
GKT, University of London Winter Meeting December 2003 |
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Infusion
of the group III metabotropic glutamate receptor agonist L-AP4 (L-(+)-2-amino-4-phosphonobutyric
acid) blocks KCL-evoked GABA release in the rat globus pallidus
in vivo |
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Print abstractGroup III metabotropic glutamate (mGlu) receptors on GABAergic striatopallidal terminals in the globus pallidus (GP; Bradley et al., 1999) have been proposed to function as heteroreceptors. Recent in vitro electrophysiological evidence supports this suggestion since the selective group III mGlu receptor agonist L-AP4 mediates inhibition of GABA-mediated inhibitory post synaptic potentials in the GP (Valenti et al., 2003). The current study sought to provide more direct evidence for such a role by examining the ability of L-AP4 to modulate GABA release in the GP in vivo.
Male, Sprague Dawley (270-300g) rats were anaesthetised with chloral hydrate (bolus dose of 130mg kg-1 followed by maintenance doses of 16mg kg-1 as necessary) and a microdialysis probe (2 mm tip, Hospal AN 69 membrane) was implanted into the GP (0.9 mm posterior, 3.0 mm lateral and 0.74 mm ventral to bregma). Probes were perfused with aCSF at a rate of 1 µl min-1 and one hour after probe implantation, collection of 20-min fractions commenced. Following collection of baseline fractions, animals were then perfused after 80 min for a 40-min period with either aCSF containing 300 µM L-AP4 (n=6) or aCSF alone (n=6). During the last 10-min period of this perfusion, 100 mM KCl was included in the dialysate of all animals and collection of fractions continued for up to 220 min. Levels of GABA in collected fractions were analysed by HPLC with electrochemical detection. Basal GABA release was averaged from the first three samples and subsequent fractions were expressed as a % of basal release. Data were compared using an unpaired t-test.
Basal extracellular GABA levels were consistent between groups (control group, 1.66 ± 0.12; L-AP4 group 1.82 ± 0.21 pmol 20 µl-1). Compared to vehicle, perfusion of L-AP4 for 40 min significantly reduced subsequent KCl-evoked GABA release (P<0.05; Figure 1).
Figure 1. Effect of L-AP4 (300 µM) or vehicle on KCl (100 mM)-evoked GABA release in the GP of anaesthetised rats. Data are mean ± S.E.M. (n=6). *Indicates significant difference in release between L-AP4 and vehicle-treated rats.
These preliminary data show that L-AP4 reduces KCl-evoked GABA release in the GP in vivo and provide more direct evidence that group III mGlu receptors may act as heteroreceptors on striatopallidal terminals.
Bradley et al., (1999).
Ann. N.Y. Acad. Sci., 868, 531-534.
Valenti et al., (2003). J. Neurosci., 23(18), 7218-7226.
Funded by Merck Sharp and Dohme.