Group I mGlu receptor modulation of dopamine release in the rat striatum in vivo
Introduction
The mGlu (metabotropic glutamate) receptors comprise a family (mGlu1–mGlu8 plus a number of alternatively spliced variants; e.g., see Pin and Duvoisin, 1995) which share a number of characteristics (e.g., sequence homology, relatively large extracellular N-terminal domain) which distinguishes them from other G-protein coupled receptors. Furthermore, mainly on the basis of their primary structure and associated transduction mechanisms in artificial expression systems, but also to some extent on their pharmacology, the eight mGlu receptors can be allocated to one of three groups; mGlu1 and mGlu5 receptors belonging to group I, mGlu2 and mGlu3 receptors belonging to group II and mGlu4 and mGlu6–8 make up group III. With respect to the associated transduction systems, heterologously expressed group I mGlu receptors activate phospholipase C whereas group II and III mGlu receptors are negatively coupled to adenylate cyclase (e.g., see Pin and Duvoisin, 1995; Conn and Pin, 1997). However, with respect to the transduction systems associated with native mGlu receptors, this categorisation is likely to be an oversimplification (e.g., see Pin and Bockaert, 1995).
An increasing number of central actions mediated via mGlu receptors have been reported which indicate that the pharmacological manipulation of mGlu receptors may provide therapeutic benefit (e.g., for reviews see Nicoletti et al., 1996; Conn and Pin, 1997); although the precise mGlu receptor subtype has often been not identified due to the paucity of subtype selective ligands. In the light of mGlu receptors representing a potential novel target to alleviate the symptoms of Parkinson's disease (for review see Nicoletti et al., 1996), it is of interest that mGlu receptors mediate animal behaviour indicative of an increase in dopamine release in the striatum (Sacaan et al., 1991, Sacaan et al., 1992; Kaatz and Albin, 1995; Feeley Kearney et al., 1997). The purpose of the present study was, therefore, to investigate directly whether mGlu receptors mediate an increase in dopamine release in the rat striatum and attempt to classify the mGlu receptors mediating the response. Preliminary reports of the data have been presented to the British Pharmacological Society (Bruton et al., 1996a, Bruton et al., 1996b).
Section snippets
Animal housing
Female Wistar rats (150–250 g; Charles River), were housed in groups of four in a controlled environment; temperature 21±1°C, 40–50% humidity, under a 12 h light/dark cycle (lights on 0700–1900 h) and were given free access to food (high grade maintenance diet, SDS) and water.
Stereotaxic implantation of chronic indwelling guide cannulae for microdialysis studies
Rats were anaesthetised with ketamine (60 mg/kg, i.p.) and medetomidine (250 μg/kg, i.p.) before 5 mm chronically indwelling guide cannulae (19-gauge stainless steel tubing) were inserted stereotaxically (the tip of the
Characterisation of striatal dopamine release in vivo estimated by microdialysis
The limit of detection for dopamine quantified by HPLC-ECD was routinely between 0.6 and 3.0 pg (signal-to-noise ratio 3:1; injection volume 40 μl).
Striatal dialysate levels varied from animal to animal. Dialysate dopamine levels were therefore normalised to basal levels to assess drug effect. Basal release averaged 3.4±0.5 pg/20 min (mean±S.E.M., n=40) and was not modified by the switching of syringes to deliver a different supply of aCSF (Fig. 1). Perfusion of tetrodotoxin (1 μM; via the
Discussion
The present studies utilised the microdialysis technique to estimate striatal dopamine release in freely moving rats and assess the ability of mGlu receptors to modulate this release. The basic methodology was identical to that we had used previously to demonstrate the ability of the 5-HT4 receptor (5-hydroxytryptamine4 receptor) and the AT1 receptor (angiotensin AT1 receptor) to modulate striatal dopamine release in the rat, in vivo (Brown et al., 1996; Steward et al., 1996). Consistent with
Acknowledgements
We are grateful to Prof. Graham L. Collingridge for advice and Dr. Mark A. Wigmore for comments on the manuscript.
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