Metabotropic glutamate mGlu5 receptor-mediated modulation of the ventral striopallidal GABA pathway in rats. Interactions with adenosine A2A and dopamine D2 receptors

Dı́az-Cabiale, Zaida; Vivó, Meritxell; Arco, Alberto Del; O’Connor, W.T.; Harte, Michael K.; Müller, Christian; Martı́nez, Emili; Popoli, Patrizia; Fuxé, Kjell; Ferré, Sergi

doi:10.1016/s0304-3940(02)00179-9

Cited by 116 publications

(85 citation statements)

References 20 publications

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“…For example, using microdialysis techniques, de Novellis et al, (2003) found that activation of mGluR5 by perfusion of CHPG through the dialysis probe significantly enhanced extracellular levels of GABA in the periaquaductal gray of rats. Similarly, intra-accumbens administration of CHPG increased GABA levels in the ventral pallidum (Diaz-Cabiale et al, 2002). In both studies, MPEP pretreatment blocked the agonist-induced increases in GABA levels.…”

Section: Discussionmentioning

confidence: 74%

“…GABA A a1 staining was also found on the cell bodies and processes in the same regions of the hippocampal formation (Figure 6d). The pallidal regions (ventral pallidum and globus pallidus) were also examined given that mGluR5 and GABA A a1 are expressed in those regions (Lu et al, 1999;Pirker et al, 2000;Schwarzer et al, 2001;Poisik et al, 2003) and that activation of mGluR5 in the nucleus accumbens has been shown to increase GABA levels in the ventral pallidum (Diaz-Cabiale et al, 2002), suggesting a potential interaction between the two receptor systems in this brain area. In the present work, intense staining of both GABA A a1 and mGluR5 was found on cell bodies and processes in the ventral pallidum (Figure 6g and h) and the globus pallidus ( Figure 6j and k).…”

Section: Immunohistochemistry With Confocal Microscopymentioning

confidence: 99%

“…For example, positive modulators of GABA A receptors, such as barbiturates, benzodiazepines, and neurosteroids, produce ethanollike stimulus effects (Ator et al, 1993;Barry, 1991;Evans and Balster, 1991;Grant et al, 1996Grant et al, , 1997Jarbe and McMillan, 1983;Shelton and Grant, 2002) in multiple species. MGluR5 activity has the potential to influence ethanol discrimination based on evidence that mGluR5 can influence GABA neurotransmission (de Novellis et al, 2003;Hoffpauir and Gleason, 2002;Diaz-Cabiale et al, 2002). For example, the mGluR5 agonist CHPG has been shown to increase GABA levels in vivo and antagonism of mGlu5 receptors blocks the CHPG-induced increases in GABA (de Novellis et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological and Anatomical Evidence for an Interaction Between mGluR5- and GABAA α1-Containing Receptors in the Discriminative Stimulus Effects of Ethanol

Besheer

Hodge

2004

Neuropsychopharmacol

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The discriminative stimulus properties of ethanol are mediated in part by positive modulation of GABA A receptors. Recent evidence indicates that metabotropic glutamate receptor subtype 5 (mGluR5) activity can influence GABA A receptor function. Therefore, the purpose of this work was to examine the potential involvement of mGluR5 in the discriminative stimulus effects of ethanol. In rats trained to discriminate ethanol (1 g/kg, intragastric gavage (i.g.)) from water, 2-methyl-6-(phenylethyl)-pyridine (MPEP) (1-50 mg/kg, i.p.) a selective noncompetitive antagonist of the mGlu5 receptor did not produce ethanol-like stimulus properties. However, pretreatment with MPEP (30 mg/kg) reduced the stimulus properties of ethanol as indicated by significant reductions in ethanol-appropriate responding, specifically at 0.5 and 1 g/kg ethanol, and a failure of ethanol test doses (1 and 2 g/kg) to fully substitute for the ethanol training dose. To test whether mGluR5 antagonism altered the GABA A receptor component of the ethanol stimulus, the ability of MPEP to modulate pentobarbital and diazepam substitution for ethanol was assessed. Pentobarbital substitution (1-10 mg/kg, i.p.) for ethanol was not altered by MPEP pretreatment. However, MPEP pretreatment inhibited the ethanol-like stimulus properties of diazepam (5 mg/ kg, i.p.). To examine a potential anatomical basis for these pharmacological findings, expression patterns of mGluR5-and benzodiazepinesensitive GABA A a1-containing receptors were examined by dual-label fluorescent immunohistochemistry with visualization by confocal microscopy. Results indicated that mGluR5-and GABA A a1-containing receptors were both coexpressed in limbic brain regions and colocalized on the same cells in specific brain regions including the amygdala, hippocampus, globus pallidus, and ventral pallidum. Together, these findings suggest an interaction between mGluR5-and benzodiazepine-sensitive GABA A receptors in mediating ethanol discrimination.

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Section: Discussionmentioning

confidence: 74%

Section: Immunohistochemistry With Confocal Microscopymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pharmacological and Anatomical Evidence for an Interaction Between mGluR5- and GABAA α1-Containing Receptors in the Discriminative Stimulus Effects of Ethanol

Besheer

Hodge

2004

Neuropsychopharmacol

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“…Since these A 2A -mGlu 5 -D 2 receptor interactions can be demonstrated in animal models of Parkinson's disease [58,59], we postulated that co-administration of A 2A and mGlu 5 receptor antagonists could be used as a therapeutic strategy in this disease [58]. Similarly, in vivo microdialysis experiments have shown that A 2A -mGlu 5 -D 2 receptor interactions modulate the function of the GABAergic enkephalinergic neurons of the nucleus accumbens [60], which can have implications for schizophrenia and drug addiction.…”

Section: Coexistence Of the Reciprocal Antagonistic A 2a -D 2 Receptomentioning

confidence: 99%

An Update on Adenosine A2A-Dopamine D2 Receptor Interactions: Implications for the Function of G Protein-Coupled Receptors

Ferré¹,

Quiroz²,

Woods³

et al. 2008

CPD

225

185

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Adenosine A2A-dopamine D2 receptor interactions play a very important role in striatal function. A2A-D2 receptor interactions provide an example of the capabilities of information processing by just two different G protein-coupled receptors. Thus, there is evidence for the coexistence of two reciprocal antagonistic interactions between A2A and D2 receptors in the same neurons, the GABAergic enkephalinergic neurons. An antagonistic A2A-D2 intramembrane receptor interaction, which depends on A2A-D2 receptor heteromerization and Gq/11-PLC signaling, modulates neuronal excitability and neurotransmitter release. On the other hand, an antagonistic A2A-D2 receptor interaction at the adenylyl-cyclase level, which depends on Gs/olf-and Gi/o-type V adenylyl-cyclase signaling, modulates protein phosphorylation and gene expression. Finally, under conditions of upregulation of an activator of G protein signaling (AGS3), such as during chronic treatment with addictive drugs, a synergistic A2A-D2 receptor interaction can also be demonstrated. AGS3 facilitates a synergistic interaction between Gs/olf -and Gi/o-coupled receptors on the activation of types II/IV adenylyl cyclase, leading to a paradoxical increase in protein phosphorylation and gene expression upon co-activation of A2A and D2 receptors. The analysis of A2-D2 receptor interactions will have implications for the pathophysiology and treatment of basal ganglia disorders and drug addiction.Key Words: Adenosine A 2A Receptor, Dopamine D 2 Receptor, G Protein-Coupled Receptors, Receptor Heteromers, Striatum, Basal Ganglia Disorders, Drug Addiction. LOCALIZATION OF THE A 2A -D 2 RECEPTOR HETERO-MERApplying a broad definition of "neurotransmitter" [1], adenosine can be considered as an important neurotransmitter in the CNS, which acts through different subtypes of G protein-coupled receptors (GPCRs). From the four cloned adenosine receptors (adenosine A 1 , A 2A , A 2B and A 3 receptors ) , A 1 and A 2A receptors are the main targets for the physiological effects of adenosine in the brain [2]. A 1 receptor is widely distributed in the brain, including the striatum, while A 2A receptor is mostly concentrated in the striatum [2,3]. It is becoming increasingly obvious that the modulatory role of adenosine in the striatum is related to the ability of A 1 and A 2A receptors to heteromerize with themselves and with other GPCRs, such as dopamine, glutamate, cannabinoid and ATP receptors [4][5][6][7][8][9][10][11][12][13][14]. The present review focuses on the role of one particular adenosine receptor heteromer, the one constituted by the A 2A and the dopamine D 2 receptor, which is already having important implications for the treatment of neuropathologies involving the striatum (see below).Striatal medium spiny neurons are GABAergic efferent neurons which constitute more that 95% of the striatal neuronal population. They receive two main afferents, cortical-limbic-thalamic glutamatergic inputs and dopaminergic mesencephalic inputs, from the substantia nigra pars compac...

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“…Therefore, it is rational to hypothesize that both A 2A and mGlu 5 receptors antagonist may alleviate the increased activity of the striatal neurons projection to the GP which, in turn, would result in the stimulation of thalamic glutamatergic projections to the cortex and then to the striatum. Electrophysiological studies have reported that adenosine A 2A receptors may control the GABA-evoked overflow in striatum and globus pallidus (Corsi et al, 1999;Kirk and Richardson, 1994;Mayfield et al, 1993), and synergistically increase the pallidal GABA levels when agonists acting at both A 2A /mGlu 5 receptors are coinjected (Diaz-Cabiale et al, 2002). The systemic injection of CSC is known to reverse the catalepsy produced by the bilateral blockade of D 2 DA receptors in the striatum with sulpiride (Hauber et al, 2001) and to decrease contralateral rotation induced by intrastriatal and intrasubthalamic nucleus administration of a nonselective groups I and II mGlu receptors agonist, 1S,3R-ACPD (Feeley-Kearney and Albin, 1995).…”

Section: Functional Interaction Between a 2a And Mglu 5 Receptorsmentioning

confidence: 99%

Simultaneous Blockade of Adenosine A2A and Metabotropic Glutamate mGlu5 Receptors Increase their Efficacy in Reversing Parkinsonian Deficits in Rats

Coccurello

Breysse

Amalric

2004

Neuropsychopharmacol

118

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Recent evidence suggest that antagonism of adenosine A 2A receptors represent an alternative therapeutic approach to Parkinson's disease (PD). Coactivation of A 2A and the glutamate subtype 5 metabotropic receptors (mGlu 5 ) synergistically stimulates DARPP-32 phosphorylation and c-fos expression in the striatum. This study therefore tested the effects of a joint blockade of these receptors to alleviate the motor dysfunction in a rat model of PD. 6-Hydroxydopamine infusions in the striatum produced akinetic deficits in rats trained to release a lever after a stimulus in a reaction time (RT) task. At 2 weeks after the lesion, A 2A and mGlu 5 receptors selective antagonists 8-(3-chlorostyryl)caffeine (CSC) and 2-methyl-6-(phenylethynyl)-pyridine (MPEP) were administered daily for 3 weeks either as a single or joint treatment. Injections of CSC (1.25 mg/kg) and MPEP (1.5 mg/kg) separately or in combination reduced the increase of delayed responses and RTs induced by 6-OHDA lesions, while the same treatment had no effect in controls. Furthermore, coadministration of lower doses of 0.625 mg/kg CSC and 0.375 mg/kg MPEP noneffective as a single treatment promoted a full and immediate recovery of akinesia, which was found to be more efficient than the separate blockade of these receptors. These results demonstrate that the combined inactivation of A 2A and mGlu 5 receptor potentiate their beneficial effects supporting this pharmacological strategy as a promising anti-Parkinsonian therapy.

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Metabotropic glutamate mGlu5 receptor-mediated modulation of the ventral striopallidal GABA pathway in rats. Interactions with adenosine A2A and dopamine D2 receptors

Cited by 116 publications

References 20 publications

Pharmacological and Anatomical Evidence for an Interaction Between mGluR5- and GABAA α1-Containing Receptors in the Discriminative Stimulus Effects of Ethanol

Pharmacological and Anatomical Evidence for an Interaction Between mGluR5- and GABAA α1-Containing Receptors in the Discriminative Stimulus Effects of Ethanol

An Update on Adenosine A2A-Dopamine D2 Receptor Interactions: Implications for the Function of G Protein-Coupled Receptors

Simultaneous Blockade of Adenosine A2A and Metabotropic Glutamate mGlu5 Receptors Increase their Efficacy in Reversing Parkinsonian Deficits in Rats

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