Lack of tolerance to motor stimulant effects of a selective adenosine A2A receptor antagonist

Halldner, Linda; Lozza, Gianluca; Lindström, Karin; Fredholm, Bertil B.

doi:10.1016/s0014-2999(00)00682-8

Cited by 49 publications

(27 citation statements)

References 31 publications

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“…The reversal of the akinetic deficits showed in the present study by a 3-week treatment with CSC constitute the first demonstration that the chronic A 2A receptors blockade is able to improve motor control without eliciting any side effects nor tolerance. This result is consistent with the idea that tolerance following repeated caffeine or theophylline treatment ) mostly involves adenosine A 1 receptors and indirectly the D 1 DA receptors Halldner et al, 2000).…”

Section: Adenosine a 2a Receptors Antagonism As Anti-parkinsonian Strsupporting

confidence: 91%

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

Coccurello

Breysse

Amalric

2004

Neuropsychopharmacol

117

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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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Section: Adenosine a 2a Receptors Antagonism As Anti-parkinsonian Strsupporting

confidence: 91%

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

Coccurello

Breysse

Amalric

2004

Neuropsychopharmacol

117

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“…The present results with MSX-3 agree with recent findings that indicate that tolerance does not develop to A 2A receptor antagonists (Halldner et al, 2000). Also, in unilaterally 6-OH-dopamine-lesioned rats, chronic treatment with caffeine or repeated administration of the A 2A receptor antagonist SCH 58261 was not associated with tolerance to the potentiating effects of the A 2A antagonist on turning behavior induced by dopamine agonists (Popoli et al, 2000;Pinna et al, 2001).…”

supporting

confidence: 92%

Involvement of Adenosine A1 and A2A Receptors in the Motor Effects of Caffeine after its Acute and Chronic Administration

Karcz-Kubicha¹,

Αντωνίου²,

Terasmaa

et al. 2003

Neuropsychopharmacol

177

189

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The involvement of adenosine A 1 and A 2A 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 A 1 receptor agonist CPA and the A 2A receptor agonist CGS 21680 by caffeine, the selective A 1 receptor antagonist CPT, and the A 2A 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 motoractivating effects of acutely administered caffeine in rats involve the central blockade of both A 1 and A 2A 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 crosstolerance to CPT. The present results suggest that development of tolerance to the effects of A 1 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 A 2A receptor blockade.

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“…This consideration is prompted by the well documented phenomenon of tolerance to the motor effects of the nonspecific adenosine receptor antagonist caffeine (for review, see Fredholm et al, 1999). However, several studies have now shown that the motor activation induced by a specific A 2A receptor antagonist shows no tolerance after chronic intermittent administration (Halldner et al, 2000;Pinna et al, 2001). Moreover, in a preliminary study the locomotor response to self-administered intravenous cocaine showed no tolerance in A 2A KO mice, in contrast to the marked tolerance that develops in their WT littermates (Rocha et al, 2001).…”

Section: Discussion the A 2a Adenosine Receptor Is Required For L-dopmentioning

confidence: 99%

Persistent Behavioral Sensitization to Chronic l-DOPA Requires A_2AAdenosine Receptors

et al. 2002

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To investigate the role of A 2A adenosine receptors in adaptive responses to chronic intermittent dopamine receptor stimulation, we compared the behavioral sensitization elicited by repeated L-DOPA treatment in hemiparkinsonian wild-type (WT) and A 2A adenosine receptor knock-out (A 2A KO) mice. Although the unilateral nigrostriatal lesion produced by intrastriatal injection of 6-hydroxydopamine was indistinguishable between WT and A 2A KO mice, they developed strikingly different patterns of behavioral sensitization after daily treatment with low doses of L-DOPA for 3 weeks. WT mice initially displayed modest contralateral rotational responses and then developed progressively greater responses that reached a maximum within 1 week and persisted for the duration of the treatment. In contrast, any rotational behavioral sensitization in A 2A KO mice was transient and completely reversed within 2 weeks. Similarly, the time to reach the peak rotation was progressively shortened in WT mice but remained unchanged in A 2A KO mice. Furthermore, daily L-DOPA treatment produced gradually sensitized grooming in WT mice but failed to induce any sensitized grooming in A 2A KO mice. Finally, repeated L-DOPA treatment reversed the 6-OHDA-induced reduction of striatal dynorphin mRNA in WT but not A 2A KO mice, raising the possibility that the A 2A receptor may contribute to L-DOPA-induced behavioral sensitization by facilitating adaptations within the dynorphinexpressing striatonigral pathway. Together these results demonstrate that the A 2A receptor plays a critical role in the development and particularly the persistence of behavioral sensitization to repeated L-DOPA treatment. Furthermore, they raise the possibility that the maladaptive dyskinetic responses to chronic L-DOPA treatment in Parkinson's disease may be attenuated by A 2A receptor inactivation. Key words: A 2A adenosine receptor; L-DOPA; behavioral sensitization; Parkinson's disease; dyskinesia; dynorphinFor Ͼ30 years the dopamine precursor L-DOPA has been the most effective and commonly prescribed treatment for Parkinson's disease (PD). Despite its considerable symptomatic motor benefit, chronic administration of L-DOPA leads to abnormal motor responses known as dyskinesias, involving involuntary choreic or dystonic movements in Ͼ50% of patients (5 years after the initiation of the treatment) (Chase, 1998;Obeso et al., 2000). Such shortcomings of L-DOPA and other dopaminergic drugs have prompted a search for alternative treatment strategies that provide symptomatic benefits while avoiding the delayed motor complications associated with the long-term use of antiparkinsonian drugs. Several neurotransmitters have been implicated in the motor complications elicited by repeated dopamine receptor stimulation, including glutamate (Marin et al., 1996;Tzschentke and Schmidt, 1998;Calabresi et al., 2000), cannabinoids (Souilhac et al., 1995;Zeng et al., 1999), opioids (Henry and Brotchie, 1996), and adenosine (Richardson et al., 1997;Kanda et al., 2000;Jenner, 2000). Recent...

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Lack of tolerance to motor stimulant effects of a selective adenosine A2A receptor antagonist

Cited by 49 publications

References 31 publications

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

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

Involvement of Adenosine A1 and A2A Receptors in the Motor Effects of Caffeine after its Acute and Chronic Administration

Persistent Behavioral Sensitization to Chronic l-DOPA Requires A_2AAdenosine Receptors

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Lack of tolerance to motor stimulant effects of a selective adenosine A2A receptor antagonist

Cited by 49 publications

References 31 publications

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

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

Involvement of Adenosine A1 and A2A Receptors in the Motor Effects of Caffeine after its Acute and Chronic Administration

Persistent Behavioral Sensitization to Chronic l-DOPA Requires A2AAdenosine Receptors

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Persistent Behavioral Sensitization to Chronic l-DOPA Requires A_2AAdenosine Receptors