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Adenosine A2A receptor stimulation enhances striatal extracellular glutamate levels in rats.

The influence of CGS 21680, an adenosine A2A receptor agonist, on striatal glutamate extracellular levels was tested in a microdialysis study in rats. CGS 21680 (10 mu M), infused intrastriatally through the microdialysis probe, greatly enhanced glutamate extracellular levels. These results show that striatal adenosine A2A receptors are involved in the regulation of striatal glutamate extracellular levels. They also suggest that adenosine A2A receptor antagonists may possess neuroprotective effects in models of striatal excitotoxicity.

Involvement of adenosine A1 and A2A receptors in the motor effects of caffeine after its acute and chronic administration.

The involvement of adenosine A1 and A2A receptors in the motor effects of caffeine is still a matter of debate. In the present study, counteraction of the motor-depressant effects of the selective A1 receptor agonist CPA and the A2A receptor agonist CGS 21680 by caffeine, the selective A1 receptor antagonist CPT, and the A2A receptor antagonist MSX-3 was compared. CPT and MSX-3 produced motor activation at the same doses that selectively counteracted motor depression induced by CPA and CGS 21680, respectively. Caffeine also counteracted motor depression induced by CPA and CGS 21680 at doses that produced motor activation. However, caffeine was less effective than CPT at counteracting CPA and even less effective than MSX-3 at counteracting CGS 21680. On the other hand, when administered alone in habituated animals, caffeine produced stronger motor activation than CPT or MSX-3. An additive effect on motor activation was obtained when CPT and MSX-3 were coadministered. Altogether, these results suggest that the motor-activating effects of acutely administered caffeine in rats involve the central blockade of both A1 and A2A receptors. Chronic exposure to caffeine in the drinking water (1.0 mg/ml) resulted in tolerance to the motor effects of an acute administration of caffeine, lack of tolerance to amphetamine, apparent tolerance to MSX-3 (shift to the left of its ‘bell-shaped’ dose–response curve), and true cross-tolerance to CPT. The present results suggest that development of tolerance to the effects of A1 receptor blockade might be mostly responsible for the tolerance to the motor-activating effects of caffeine and that the residual motor-activating effects of caffeine in tolerant individuals might be mostly because of A2A receptor blockade.

The Selective mGlu5 Receptor Agonist CHPG Inhibits Quinpirole-Induced Turning in 6-Hydroxydopamine-Lesioned Rats and Modulates the Binding Characteristics of Dopamine D2 Receptors in the Rat Striatum ☆: Interactions with Adenosine A2a Receptors

In 6-hydroxydopamine-lesioned rats, the selective mGlu5 receptor agonist (RS)-2-Cholro-5-Hydroxyphenylglycine (CHPG, 1-6 μg/10 μl intracerebroventricularly) significantly inhibited contralateral turning induced by quinpirole and, to a lesser extent, that induced by SKF 38393. The inhibitory effects of CHPG on quinpirole-induced turning were significantly potentiated by an adenosine A2A receptor agonist (CGS 21680, 0.2 mg/kg IP) and attenuated by an A2A receptor antagonist (SCH 58261, 1 mg/kg IP). In rat striatal membranes, CHPG (100–1,000 nM) significantly reduced the affinity of the high-affinity state of D2 receptors for the agonist, an effect potentiated by CGS 21680 (30 nM). These results show the occurrence of functional interactions among mGlu5, adenosine A2A, and dopamine D2 receptors in the regulation of striatal functioning, and suggest that mGlu5 receptors may be regarded as alternative/integrative targets for the development of therapeutic strategies in the treatment of Parkinsons disease.

Adenosine A1 receptor blockade selectively potentiates the motor effects induced by dopamine D1 receptor stimulation in rodents

An antagonistic interaction between adenosine A1 and dopamine D1 receptors has previously been found in the basal ganglia. However, direct evidence for a selective adenosine A1 antagonist-induced potentiation of dopamine D1-mediated motor activation is lacking. The systemic administration of the adenosine A1 antagonist 8-cyclopentyl-1,3-dimethylxanthine significantly potentiated the motor activating properties of the systemically administered dopamine D1 agonist SKF 38393 in both reserpinized mice and unilaterally 6-hydroxy-dopamine-lesioned rats. However, 8-cyclopentyl-1, 3-dimethylxanthine did not modify the motor effects of the dopamine D2 agonist quinpirole. The present work shows that an antagonistic interaction between adenosine A1 and dopamine D1 receptors may be involved in the motor activating effects of adenosine antagonists, like caffeine.

Adenosine A1 and A2A receptor antagonists stimulate motor activity: evidence for an increased effectiveness in aged rats

The motor effects of selective adenosine A1 and A2A receptor antagonists were tested in young (2 months) and aged (24 months) Wistar rats. In young rats, both the selective A2A receptor antagonist 5-amino-7-(2-phenylethyl)-2-2(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazo++ + lo[1,5-c]pyrimidine (SCH 58261, minimal effective dose 2 mg/kg intraperitoneally (i.p.)) and the selective A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT, minimal effective dose 1.2 mg/kg i.p.) stimulated motor activity. In old rats, both compounds induced significant motor activation starting from doses lower than those required in young animals. Specifically, the minimal effective doses of SCH 58261 and CPT in aged rats were 1 and 0.6 mg/kg i.p, respectively. The results indicate that both adenosine A1 and A2A receptors play a functional role in the control of motor activity, and, therefore, the blockade of both receptor subtypes is involved in the motor stimulating properties of methylxanthines. Also the evidence indicates, for the first time, that in aged animals the motor inhibitory adenosinergic tone seems to be increased with respect to young animals.

Adenosine A2A receptor antagonists prevent the increase in striatal glutamate levels induced by glutamate uptake inhibitors

Active uptake by neurons and glial cells is the main mechanism for maintaining extracellular glutamate at low, non‐toxic concentrations. Activation of adenosine A2A receptors increases extracellular glutamate levels, while A2A receptor antagonists reduce stimulated glutamate outflow. Whether a modulation of the glutamate uptake system is involved in the effects elicited by A2A receptor blockers has never been investigated. This study examined the ability of adenosine A2A receptor antagonists to prevent the increase in glutamate levels induced by blockade of the glutamate uptake. In rats implanted with a microdialysis probe in the dorsal striatum, perfusion with 4 mm l‐trans‐pyrrolidine‐2,4‐dicarboxylic acid (PDC, a transportable competitive inhibitor of glutamate uptake), or 10 mm dihydrokainic acid (DHK, a non‐transportable competitive inhibitor that mainly blocks the glial glutamate transporter GLT‐1), significantly increased extracellular glutamate levels. The effects of PDC and DHK were completely prevented by the adenosine A2A receptor antagonists SCH 58261 (0.01 mg/kg i.p.) and/or ZM 241385 (5 nm via probe). Since an impairment in glutamate transporter function is thought to play a major role in neurodegenerative disorders, the regulation of glutamate uptake may be one of the mechanisms of the neuroprotective effects of A2A receptor antagonists.

Effects of SCH 58261, an Adenosine A2A Receptor Antagonist, on Quinpirole-Induced Turning in 6-Hydroxydopamine-Lesioned Rats: Lack of Tolerance after Chronic Caffeine Intake

In unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats, a rodent model of Parkinsons disease (PD), the adenosine A2A receptor antagonist SCH 58261 significantly increased (+180%, p < .01) the number of rotations induced by a low dose of quinpirole (a dopamine D2 receptor agonist), while it did not significantly modify the effects of a comparably low dose of SKF 38393 (a dopamine D1 receptor agonist). The dose-dependent potentiating effects of SCH 58261 on quinpirole-induced turning were similar in caffeine-treated rats (1 g/l in drinking water over 14 days) and control animals (tap water). The selective potentiating effects of SCH 58261 on D2-dependent turning confirm the existence of a potent and specific A2A/D2 receptor-receptor interaction. The persistence of the potentiating effects of SCH 58261 after chronic caffeine intake suggests that no tolerance should develop towards the antiparkinsonian effects of adenosine A2A receptor antagonists with chronic treatment.

The mGlu5 receptor agonist CHPG stimulates striatal glutamate release: possible involvement of A2A receptors.

The intrastriatal perfusion of the selective metabotropic glutamate (mGlu)5 receptor agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG, 1000 μM) significantly increased (∼+100%, p < 0.05) glutamate extracellular levels with respect to basal values. The potentiating effect of CHPG was prevented by the selective mGlu5 receptor antagonist 2-methyl-6(phenyl-ethynyl)-pyridine (MPEP, 250 μM)) and by the adenosine A2A receptor antagonist SCH 58261 (2 mg/kg, i.p.). The results show that mGlu5 receptors are involved in the regulation of striatal glutamate release and suggest an involvement of adenosine A2A receptors in mGlu5 receptor-mediated effects.

The intrastratial injection of an adenosine A2 receptor antagonist prevents frontal cortex EEG abnormalities in a rat model of Huntington's disease

The influence of 3,7-dimethyl-1-propargylxanthine (DMPX) an adenosine A(2) receptor antagonist, was studied in the quinolinic acid (QA) model of Huntingtons disease. Male Wistar rats received bilateral intrastriatal injections of QA (300 nmol) alone or plus DMPX (0.02, 0.2 and 2 microg). At the dose of 0.2 microg, DMPX completely prevented QA-induced EEG abnormalities at the level of frontal cortex. The results support the hypothesis of a neuroprotective role of adenosine A(2) receptor antagonists.

Neuroprotective effects of the mGlu5R antagonist MPEP towards quinolinic acid-induced striatal toxicity: involvement of pre- and post-synaptic mechanisms and lack of direct NMDA blocking activity.

The aim of this work was to investigate the potential neuroprotective effects of the metabotropic glutamate receptor 5 (mGlu5R) antagonist 2‐Methyl‐6‐(phenylethynyl)‐pyridine (MPEP) towards quinolinic acid (QA)–induced striatal excitoxicity. Intrastriatal MPEP (5 nmol/0.5 µL) significantly attenuated the body weight loss, the electroencephalographic alterations, the impairment in spatial memory and the striatal damage induced by bilateral striatal injection of QA (210 nmol/0.7 µL). In a second set of experiments, we aimed to elucidate the mechanisms underlying the neuroprotective effects of MPEP. In microdialysis studies in naive rats MPEP (80–250 µm through the dialysis probe) significantly reduced the increase in glutamate levels induced by 5 mm QA. In primary cultures of striatal neurons MPEP (50 µm) reduced the toxicity induced by direct application of glutamate [measured as release of lactate dehydrogenase [LDH]). Finally, we found that 50 µm MPEP was unable to directly block NMDA‐induced effects (namely field potential reduction in corticostriatal slices, as well as LDH release and intracellular calcium increase in striatal neurons). We conclude that: (i) MPEP has neuroprotective effects towards QA‐induced striatal excitotoxicity; (ii) both pre‐ and post‐synaptic mechanisms are involved; (iii) the neuroprotective effects of MPEP do not appear to involve a direct blockade of NMDA receptors.