Adenosine A_2A and group I metabotropic glutamate receptors synergistically modulate the binding characteristics of dopamine D₂ receptors in the rat striatum

Abstract

There is experimental evidence for the existence of interactions between metabotropic glutamate (mGlu), adenosine and dopamine receptors in the striatum. In membrane preparations from rat striatum the group I and II mGlu receptor agonist 1-aminocyclopentane-1S-3R-dicarboxylic acid (1S-3R-ACPD) was found to modulate the binding characteristics of D₂ receptors in a similar manner as the A_2A receptor agonist 2-[p-(2-carboxyethyl)phenthylamino]-5′-N-ethylcarboxamidoadenosine (CGS 21680), with a significant decrease in the affinity of the high-affinity state of D₂ receptors for dopamine. The effect of 1S-3R-ACPD was mimicked by (±)-trans-ACPD (t-ACPD; a racemic mixture of 1S-3R-ACPD and its inactive isomer 1R-3S-ACPD) and by the selective group I mGlu receptor agonist 3,5-dihydroxyphenylglycine (DHPG) and it was counteracted by the selective group I mGlu receptor antagonist 1-aminoindan-1,5-dicarboxilic acid (AIDA), but not by the the group II and III mGlu receptor antagonist (RS)-α-methyl-4-tetrazolylphenylglycine (MTPG) or the adenosine receptor antagonist 8-phenyltheophylline. Furthermore, a strong synergistic effect was observed when the striatal membranes were exposed to both CGS 21680 and 1S-3R-ACPD. In agreement with the biochemical results, in unilaterally 6OHdopamine lesioned rats 1S-3R-ACPD counteracted the turning behaviour induced by the D₂ receptor agonist quinpirole, but not by the D₁ receptor agonist SKF 38393, and it synergistically potentiated the antagonistic effect of CGS 21680 on quinpirole-induced turning behaviour.

Introduction

Several different metabotropic glutamate (mGlu) receptors have been cloned, which according to structural, functional and pharmacological properties have been subcategorized in three different groups. Stimulation of phospholipase C is a main transduction mechanism for group I mGlu receptors (mGluR1 and mGluR5) and activation of group II mGlu receptors (mGluR2 and mGluR3) and group III mGlu receptors (mGluR4, mGluR6 and mGluR7) results in inhibition of adenylyl cyclase (Nakanishi, 1992, Schoepp and Conn, 1993, Pin and Duvoisin, 1995). In general it can be assumed that activation of group I mGlu receptors increases and activation of group II or group III mGlu receptors decreases neuronal excitation (Nicoletti et al., 1996).

The striatum contains one of the highest densities of mGlu receptors in the brain (Albin et al., 1992) and expresses mRNA for the three different groups of mGlu receptors (Testa et al., 1994). Striatal group II and group III mGlu receptors seem to be mainly presynaptic and involved in the modulation of glutamate release (East et al., 1995, Calabresi et al., 1996). Striatal group I mGlu receptors, on the other hand, are most probably postsynaptic (Martin et al., 1992, Shigemoto et al., 1993) and they have been shown to be involved in long-term regulation of corticostriatal synaptic transmission, like striatal long-term depression (Calabresi et al., 1996). Striatal mGlu receptors have been suggested to be involved in different behavioural effects of 1S-3R-ACPD in the rat. The striatal administration of 1S-3R-ACPD induces a contralateral turning behaviour (Sacaan et al., 1991, Sacaan et al., 1992, Kaatz and Albin, 1995), which seems to be mediated by group I mGlu receptors (Kearney et al., 1997). Furthermore, it has been reported that the intracerebroventricular administration of 1S-3R-ACPD induces motor depression and catalepsy and counteracts amphetamine-induced motor activation (Kronthaler and Schmidt, 1996), while the infusion in the nucleus accumbens induces motor activation and potentiates amphetamine-induced motor activity (Attarian and Amalric, 1997).

Much experimental data suggest the existence of functionally important interactions between adenosine and dopamine receptors in the basal ganglia (Ferré et al., 1992, Ferré et al., 1997). Adenosine A_2A and A₁ receptors selectively and antagonistically modulate the binding and functional characteristics of dopamine D₂ and D₁ receptors, respectively. The A_2A–D₂ interaction takes place mainly in the GABAergic striopallidal neuron (Ferré et al., 1993, Pollack and Fink, 1995, Mayfield et al., 1996), where these two receptors are colocalized (Schiffmann et al., 1991, Fink et al., 1992). Dopamine and adenosine A_2A receptors have been suggested to be involved in the turning behaviour induced by striatal group I mGlu receptors, since it can be counteracted by dopamine depletion or the administration of dopamine or adenosine A_2A receptor antagonists and potentiated by the adenosine A_2A receptor agonists (Sacaan et al., 1992, Kearney and Albin, 1995, Kearney et al., 1997). Therefore, interactions between striatal group I mGlu receptors and adenosine A_2A and dopamine D₂ receptors might underlie some of the behavioural effects induced by activation of group I mGlu receptors. In the present work biochemical and behavioral evidence for this hypothesis was found.