Group I mGlu receptor modulation of dopamine release in the rat striatum in vivo

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Abstract

The present study investigated the ability of mGlu (metabotropic glutamate) receptor to modulate dopamine release in the striatum of freely moving rats assessed using the microdialysis technique. The group I and II mGlu receptor agonist (1S,3R)-ACPD (1-amino-cyclopentane-1,3-dicarboxylate; 1–3 mM) increased dopamine release (367% of basal levels) which was prevented by the non-selective mGlu receptor antagonist, (+)-MCPG (alpha-methyl-4-carboxyphenylglycine; 10 mM). The group I mGlu receptor agonist, DHPG (3,5-dihydroxyphenylglycine; 0.3–1 mM), also increased dopamine release (maximum increase 229%) which was also antagonised by (+)-MCPG (10 mM). In contrast, the group II mGlu receptor agonist, DCG-IV (2-(2,3-dicarboxycyclopropyl)glycine; 3–50 μM), induced a more modest increase in dopamine release (156% of basal levels). Combined administration of DHPG (1 mM) and DCG-IV (50 μM) maximally increased dopamine release by 252% of basal levels which was antagonised completely by (+)-MCPG (10 mM). Such findings indicate that group I (and possibly group II) mGlu receptors facilitate rat striatal dopamine release 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.

References (36)

  • N.B. Mercuri et al.

    Activation of metabotropic glutamate receptors induces an inward current in rat dopamine mesencephalic neurons

    Neuroscience

    (1993)
  • F. Nicoletti et al.

    Metabotropic glutamate receptors: a new target for the therapy of neurodegenerative disorders?

    Trends Neurosci.

    (1996)
  • M. Ohno et al.

    Persistent increase in dopamine release following activation of metabotropic glutamate receptors in the rat nucleus accumbens

    Neurosci. Lett.

    (1995)
  • J.-P. Pin et al.

    Get receptive to metabotropic glutamate receptors

    Curr. Op. Neurobiol.

    (1995)
  • J.-P. Pin et al.

    The metabotropic glutamate receptors: structure and functions

    Neuropharmacology

    (1995)
  • N.M. Barnes et al.

    Differential modulation of extracellular levels of 5-hydroxytryptamine in the rat frontal cortex by (R)- and (S)-zacopride

    Br. J. Pharmacol.

    (1992)
  • D.C. Brown et al.

    Ability of angiotensin II to modulate striatal dopamine release via the AT1 receptor in vitro and in vivo

    Br. J. Pharmacol.

    (1996)
  • R.K. Bruton et al.

    Elevation of in vivo striatal dopamine release in the rat via activation of metabotropic glutamate receptors

    Br. J. Pharmacol.

    (1996)
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