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Effects of SCH 58261, an Adenosine A2A Receptor Antagonist

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Effects of SCH 58261, an Adenosine A2A Receptor Antagonist 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 Patrizia Popoli, M.D., Rosaria Reggio, and Antonella Pèzzola In unilaterally 6-hydroxydopamine (6-OHDA)-lesioned effects of SCH 58261 on D2-dependent turning confirm the rats, a rodent model of Parkinson’s disease (PD), the existence of a potent and specific A2A/D2 receptor-receptor adenosine A2A receptor antagonist SCH 58261 significantly interaction. The persistence of the potentiating effects of increased (ϩ180%, p Ͻ .01) the number of rotations SCH 58261 after chronic caffeine intake suggests that no induced by a low dose of quinpirole (a dopamine D2 receptor tolerance should develop towards the antiparkinsonian agonist), while it did not significantly modify the effects of a effects of adenosine A2A receptor antagonists with chronic comparably low dose of SKF 38393 (a dopamine D1 receptor treatment. [Neuropsychopharmacology 22:522–529, agonist). The dose-dependent potentiating effects of SCH 2000] © 2000 American College of 58261 on quinpirole-induced turning were similar in Neuropsychopharmacology. Published by Elsevier caffeine-treated rats (1 g/l in drinking water over 14 days) Science Inc. and control animals (tap water). The selective potentiating KEY WORDS: Adenosine A2A receptors; Dopamine D1 and D2 while predominance of the indirect or the direct path- receptors; Parkinson’s disease; Chronic caffeine treatment. ways is thought to underlie hypo- and hyper-kinetic disorders, respectively (Albin et al. 1989). For instance, The two major output pathways from the basal ganglia, over-activity of the indirect pathway (due to the reduc- the direct (striato-nigral) and the indirect (striato-pal- tion of dopamine D receptor-mediated inhibition of lidal) pathways, have opposing effects on thalamocorti- 2 striato-pallidal neurones) is thought to determine the cal neurones and subsequently on motor activity (Alex- motor deficits of Parkinson’s disease (PD) (Alexander ander and Crutcher 1990). A co-ordinated balance of and Crutcher 1990; Gerfen et al. 1990). the pathway functions results in normal movements, In the striato-pallidal neurones, dopamine D2 recep- tors are co-localized with adenosine A2A receptors (Fink et al. 1992; Schiffmann et al. 1991; Svenningsson et al. ր 1997a), and a tonic, antagonistic A2A D2 interaction has From the Pharmacology Department (PP, RR, AP), Istituto Supe- been reported. The stimulation of A receptors de- riore di Sanità Viale Regina Elena 299, 00161 Rome Italy. 2A Address correspondence to: Dr. Patrizia Popoli, Pharmacology creases the affinity of D2 receptors for the agonist in rat Department, Istituto Superiore di Sanità Viale Regina Elena 299, striatal membranes (Ferré et al. 1991b) and in a mouse 00161 Rome Italy. Tel.: ϩ39-06-49902482; Fax: ϩ39-06-49387104; fibroblast cell line stably cotransfected with A and D E-mail: [email protected] 2A 2 Received July 29, 1999; revised October 11, 1999; accepted receptors (Dasgupta et al. 1996). Adenosine A2A recep- November 11, 1999. tor agonists inhibit, while A2A receptor antagonists po- NEUROPSYCHOPHARMACOLOGY 2000–VOL. 22, NO. 5 © 2000 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/00/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(99)00144-X NEUROPSYCHOPHARMACOLOGY 2000–VOL. 22, NO. 5 SCH 58261 Potentiates Quinpirole-Induced Turning in PD Rat Model 523 tentiate, the effects of D2 receptor agonists on motor METHODS activity, neurotransmitter release and striatal c-Fos ex- Experimental Protocol pression (Ferré et al. 1991a, 1993, 1999; Jin et al. 1993; Morelli et al. 1995; Pollack and Fink 1995). While much Male Sprague-Dawley rats (145-155 g) were used. The data indicates that A2A receptors selectively interact animals were kept under standardized temperature, with dopamine D2 receptors (reviewed in Ferré et al. humidity and lighting conditions, with free access to 1997), adenosine A2A receptor blockade has been re- water and food. Animal care and use followed the di- ported to potentiate both D1- and D2-dependent con- rectives of the Council of the European Communities tralateral rotations in 6-hydroxydopamine (6-OHDA)- (86/609/EEC). Under Equithesin (3 ml/kg) anaesthe- lesioned rats (Fenu et al. 1997; Pinna et al. 1996). One of sia, animals were placed in a Kopf stereotaxic appara- the possible explanations for these findings is a syner- tus. Unilateral injections of 6-hydroxydopamine (8␮g / ␮ gistic D1-D2 interaction occurring due to a direct stimu- 4 l of 0.2% ascorbic acid saline solution) were per- lation of D1 receptors (by the D1 receptor agonist) and a formed in the left nigrostriatal pathway (coordinates ϭ Ϫ ϭ ϩ ϭ Ϫ facilitation of D2 receptors (by the removal of a tonic with respect to bregma: A 2.4; L 1.2; V 7.8 A2A-dependent inhibition). If A2A receptor blockade di- mm) by means of a Hamilton syringe (mod. 701). Start- rectly potentiated D2- mediated responses while only ing 3 weeks after the lesion, the animals’ ability to ro- indirectly potentiated D1-mediated effects, we would tate in response to apomorphine (0.05 mg/kg subcuta- expect the effects elicited by very low doses of D1 and neously) was tested. Contralateral rotations induced by D2 receptor agonists to be modulated differently by A2A apomorphine were measured 3-4 times at weekly inter- receptor blockade. vals. Only animals showing at least 50 turns/ 5 min in Due to the key role played by adenosine A2A recep- the last test were included in the study. Thirty minutes tors in the regulation of striatal dopaminergic neu- prior to starting the experiments, the animals were rotransmission, drugs acting on these receptors are placed in rotation bowls in a soundproof experimental likely to be useful in the treatment of neurological dis- room. Each trial was analysed by an observer unaware orders related to dopaminergic dysfunction (Ferré et al. of the treatment received by the animals. Only com- 1992; Ongini and Fredholm 1996). In particular, adenos- plete (360Њ) and uninterrupted turns were recorded ine A2A receptor blockade is likely to counteract over 60 min. (through the potentiation of D2 receptor-mediated ef- fects) the over-activity of the indirect pathway in PD. In Dose-response effects of Dopamine D and D fact, adenosine A receptor antagonists have recently 1 2 2A Receptor Agonists been proposed as potential new agents for treating this disease (Richardson et al. 1998). The current PD treat- The ability of different doses of SKF 38393 and quin- ment is based almost entirely on dopamine replacement pirole to induce contralateral rotations was evaluated in therapy using L-dopa but the occurrence of dyskinesia groups of 6-8 lesioned rats each. Low doses of both and/or psychosis and the loss of efficacy over time drugs (1/5 of the minimal dose inducing a maximal ef- greatly impair the therapeutic benefit of this drug. Al- fect) were selected for the subsequent experiments though adenosine A2A receptor antagonists may be a aimed at evaluating the potentiating effects of SCH very promising therapeutic alternative, tolerance may 58261. develop due to chronic administration. In fact chronic treatment with caffeine, a non-selective adenosine re- Influence of SCH 58261 on Quinpirole- and SKF ceptor antagonist, has been shown to induce tolerance 38393-Induced Turning to the motor stimulating effects of caffeine in rodents (Garrett and Holtzman 1995a,b; Nikodijevic et al. 1993a,b), Either quinpirole (0.02 mg/kg) or SKF 38393 (0.6 mg/ and to caffeine-induced c-Fos expression in the rat glo- kg) were administered intraperitoneally (i.p.) 15 min af- bus pallidus (Svenningsson and Fredholm 1997). ter SCH 58261 (2 mg/kg i.p.) or vehicle (n ϭ 8 in both The first aim of this paper was to evaluate whether groups). The dose of SCH 58261 used in these experi- SCH 58261, a selective adenosine A2A receptor antago- ments was selected on the basis of a previous study nist (Zocchi et al. 1996), influenced differently the turn- (Popoli et al. 1998). ing behavior elicited by comparably low doses of D1 (SKF 38393) and D (quinpirole) receptor agonists in 2 Chronic Caffeine Treatment rats unilaterally lesioned with 6-OHDA, a rodent model of PD (Schwarting and Huston 1996; Ungerstedt 1971). To test whether chronic caffeine intake affected the abil- Secondly, we aimed to evaluate whether the potentiat- ity of SCH 58261 to potentiate quinpirole-induced rota- ing effects of SCH 58261 were reduced by chronic ade- tions, the effects of three different doses of SCH 58261 nosine receptor blockade. were tested in both caffeine-treated and control rats. A 524 P. Popoli et al. NEUROPSYCHOPHARMACOLOGY 2000–VOL. 22, NO. 5 caffeine solution (1 g/l in drinking water) was adminis- 38393-induced rotations could merely be ascribed to the tered over 14 consecutive days to lesioned rats. The high inter-individual variability (as suggested by the dose of caffeine was chosen on the basis of previous re- large S.E.M) of the effects elicited by this dose of SKF ports (Garrett and Holtzman 1995a, b; Holtzman et al. 38393, two additional sets of experiments were per- 1991). Animals had free access to drinking bottles over formed. First, the ability of N6-cyclopenthyl-theophyl- the entire period. The daily caffeine intake was deter- line (CPT, a selective adenosine A1 receptor antagonist) mined twice a week by weighing each bottle on consec- to potentiate the turning behavior induced by SKF utive days at 9.30 A.M.; a difference of 1 g in weight was 38393 0.6 mg/kg was tested in 6 rats. CPT (7.2 mg/kg, assumed to represent 1 ml of caffeine solution con- 15 min before) increased significantly the number of sumed.
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