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

ELSEVIER

NeuroscienceLetters 218 (1996) 209-213

N[UIIIIZI L[IT[NS

Adenosine receptor blockade selectively potentiates the motor effects induced by dopamine Dx receptor stimulation in rodents P a t r i z i a P o p o l i a, L y d i a G i m 6 n e z - L l o r t b, A n t o n e l l a P e z z o l a a, R o s a r i a R e g g i o a, E m i l i M a r t f n e z b, K j e l l F u x e c, S e r g i F e r r 6 c'* aPharmacology Department, Istituto Superiore di Sanitgl, Viale Regina Elena, 299, 00161 Rome, Italy bDepartment of Neurochemistry, I.LB.B., C.S.I.C., Jordi Girona 18-26, 08034 Barcelona, Spain CDepartment of Neuroscience, Division of Cellular and Molecular Neurochemistry, Karolinska Institute, $171 77 Stockholm, Sweden

Received22 July 1996;revisedversionreceived9 September1996; accepted 3 October 1996

Abstract

An antagonistic interaction between adenosine AI and dopamine D1 receptors has previously been found in the basal ganglia. However, direct evidence for a selective adenosine AI antagonist-induced potentiation of dopamine Dl-mediated motor activation is lacking. The systemic administration of the adenosine A1 antagonist 8-cyclopentyl-l,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-l,3-dimethylxanthine did not modify the motor effects of the dopamine D2 agonist quinpirole. The present work shows that an antagonistic interaction between adenosine A~ and dopamine D1 receptors may be involved in the motor activating effects of adenosine antagonists, like caffeine. Keywords: SKF 38393; Quinpirole; Caffeine; Turning behavior; Mouse; Rat

Dopaminergic neurotransmission is involved in both the motor depressant effects of adenosine agonists and the motor activating effects of adenosine antagonists, like caffeine and theophylline (for review, see [8]). We have proposed that specific imeractions between subtypes of adenosine and dopamine striatal receptors are the main mechanism of action re,;ponsible for the motor effects of adenosine agonists and antagonists. Adenosine A1 and A2A receptors antagonistically modulate the binding, transduction and functional characteristics of dopamine D1 and D2 receptors, respectively 117-12]. The A1-D1 and A2A-D2 interactions appear to be segregated in the two types of GABAergic striatal efterent neurons [9,12,23], which make up more than 90% of the striatal neurons [1,15]. In fact, adenosine A2A and dopamine D2 receptors are colocalized in the GABAergic striopallidal neurons [13,24], while adenosine AI and dopamine Dl receptors are colocalized in the GABAergic strionigral-strioentopeduncular neurons [12]. However, it must be pointed out that adeno* Correspondingauthor. Fax: +46 8 337941.

sine Al receptors are also localized in the striopallidal neurons [12] and that the less abundant striatal cholinergic interneurons seem to contain functional dopamine D1 and D2 [5] and adenosine Az and A2A receptors [3]. In radioligand binding experiments the adenosine A1 agonist cyclopentyladenosine (CPA) was found to decrease both high affinity dopamine D1 agonist and antagonist binding in the striatum [10,11]. At the behavioral level CPA was shown to counteract the motor activation induced by dopamine DI but not D2 receptor stimulation in reserpinized mice and the dopamine D1 receptor-mediated perioral dyskinesia in rabbits [10]. Finally, CPA completely counteracted the dopamine D1 receptor-mediated facilitation of GABAergic neurotransmission in the stfioentopeduncular neuron [12]. Therefore, altogether these results show that an antagonistic interaction between adenosine A1 and dopamine D1 receptors is involved in the motor depressant effects of adenosine agonists. Although we also proposed that this AI-D1 interaction could be involved in the motor activating effects of adenosine antagonists, like the methylxanthines caffeine

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and theophylline, direct evidence for a selective adenosine A1 antagonist-induced potentiation of dopamine D1mediated motor activation was lacking. In the present study we give evidence for the selective involvement of an A~-D1 interaction in the motor stimulating effects of adenosine antagonists. The adenosine A~ antagonist 8cyclopentyl-l,3-dimethylxanthine (CPT) [4] was found to potentiate the motor activating effects induced by the dopamine D~ agonist SKF 38393, but not by the dopamine Dz agonist quinpirole in both reserpinized mice and unilaterally 6-hydroxy (6-OH)-dopamine-lesioned rats. Male mice (n = 140) of the OF1 strain, weighing 25-31 g were used. The mice were used only once. The motor activity of groups of three mice (n = 1) [2] was recorded with a video-computerized system (Videotrack 512, View Point, Lyon) by using a subtraction image analysis. The system was set to measure any kind of motor activity (locomotion, rearing, intense grooming, jumps) and to avoid monitoring of very small movements (breathing, non-intense grooming, tremor). Four cages (35.5 × 35.5 × 35.5) were simultaneously registered in a soundproof, temperature-controlled (22 + 2°C) experimental room, which was uniformly illuminated with two incandescent lamps (100 W) located 2 m above the floor. Motor activity was recorded during 1 h immediately after the animals were placed in the open-field cages without any acclimatization period. Reserpine (Sigma, St. Louis, MO, USA) was dissolved in a drop of glacial acetic acid which was made up to volume with 5.5% glucose. (+)SKF 38393 hydrochloride (RBI, Natick, MA, USA), (-)quinpirole (RBI) and CPT (RBI) were dissolved in 5.5% glucose. Reserpine (5 mg/kg s.c.) was administered 20 h before the recording of motor activity. CPT (0.3-3 mg/kg i.p) was administered alone or 15 min prior to the administration of SKF 38393 (15 mg/kg s.c.) or quinpirole (0.5 mg/kg s.c.). These doses of SKF 38393 and quinpirole were chosen according to previous studies showing their equipotency in reserpinized mice [6]. The volume of injection was 10 ml/kg. All values recorded per 10 min were transformed (square root of (counts + 0.5)) [2] and the mean of all the transformed data per three mice (n = 1) was used as the dependent variable. One-way analysis of variance (ANOVA) with Fisher's posthoc comparisons were used for statistical analysis. Male rats (n = 50) of the Sprague-Dawley strain were used. A unilateral lesion of the left nigrostriatal dopaminergic pathway was made when the weight of the animals was 145-160 g (coordinates with respect to bregma, A --4.4; L -1.2; V -7.8), by means of a stereotaxic injection of 8 /zg of 6-OH-dopamine (SIGMA) dissolved in 4 /~1 0.2% ascorbic acid saline (0.9% NaC1) solution (1 /xl/ min) under Equithesin anesthesia (3 ml/kg). Four weeks after surgery the animals were injected with apomorphine (SIGMA, 0.05 mg/kg s,c.) four times with 1 week intervals. Only animals showing at least 50 turns/5 min in the last test were included in the experiments. Thirty minutes

before the first drug administration the animals were taken to a soundproof experimental room and placed into the rotation chamber. Each trial was analyzed by an observer unaware of the treatment received by the animals. Only complete and uninterrupted turns were recorded. Animals were treated more than once and the interval between treatments was at least one week. An A - B - A design (dopamine agonist - CPT + dopamine agonist - dopamine agonist) was performed to control the reproducibility of the dopamine-agonist induced turning behavior with repeated treatment. CPT (0.3 or 0.6 mg/kg i.p.) was administered alone or 15 min before the administration of SKF 38393 (15 mg/kg s.c.) or quinpirole (0.5 mg/kg s.c.). Oneway ANOVA with Fisher's posthoc comparisons were used for statistical analysis. As previously reported, the dopamine DI agonist SKF 38393 and the dopamine D2 agonist quinpirole induced motor activity in reserpinized mice and turning behavior (contralateral to the lesion side) in unilaterally 6-OHdopamine-lesioned rats [16,20,21]. The doses of SKF 38393 (15 mg/kg) and quinpirole (0.5 mg/kg) used in the present study were equipotent in both experimental approaches (Figs 1 and 2). CPT did not produce any motor activity in reserpinized mice (up to 3 mg/kg; Fig. 1), or turning behavior in unilaterally 6-OH-dopaminelesioned rats (up to 0.6 mg/kg; data not shown). However, CPT significantly potentiated the motor activating properties of SKF 38393 in both reserpinized mice and unilaterally 6-OH-dopamine-lesioned rats. On the other hand, CPT did not modify the effects of quinpirole (Figs 1 and 2). motor activity 5 i

10 i

15 i

20

glucose CPT 0.3 CPT 3 SKF

-3

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CPT 0.3+SKF quinpirole CPT 0.3+quinpirole

I Io I Io

Fig. 1. Motor activity in reserpinized mice. Results are expressed as means + SEM of the transformed data (square root of (counts + 0.5)) obtained during all the 10 min periods from the firsthour of observation. CPT 0.3 and CPT 3, CPT 0.3 and 3 mg/kg i.p., respectively;SKF, SKF 38393 15 mg/kg s.c.; quinpirole, quinpirole 0.5 mg/kg s.c.; a, significantly different comparedto the glucose-treated group; b, significantly different comparedto the SKF 38393-treated group (one-wayANOVA with Fisher's PLSD posthoc comparisons; P < 0.05 in all cases; n = 6-8/group).

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contralateral turns/60 rain 0

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SKF

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quinpirole

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Fig. 2. Tuming behaviourin unilaterally 6-OH-dopamine-lesionedrats. Results are expressedas means + SEM of total numberof turns contralateral to the lesioned side. CPT 0.3 and CPT 0.6, CPT 0.3 and 0.6 mg/kg i.p., respectively;SKF, SICA :~38393 15 mg/kg s.c.; quinpirole, quinpirole 0.5 mg/kg s.c.; a, significaJatlydifferent compared to the SKF 38393treated group (one-way ANOVA with Fisher's PLSD posthoc comparisons; P < 0.05; n = 6/grot~p). The vast majority of striatal neurons (more than 90%) are GABAergic efferent neurons and the second most abundant neuronal population is the cholinergic interneuron (about 5%) [1,15]. There are two well-defined subtypes of striatal GABAergic efferent neurons: the striopallidal neurons, which constitute the direct striatal efferent pathway, and the strionigral and strioentopeduncular neurons, which give rise to the indirect striatal efferent pathway [1,11] (Fig. 3). The most accepted model of basal ganglia circuitry suggests that the direct and indirect pathways differentially control the output structures of the basal ganglia, i.e. the entopeduncular nucleus and the substantia nigra pars retie ulata. The direct and indirect pathways have an inhibitory and excitatory influence, respectively, on the neuronal activity of the output structures, which exert a tonic inhibitory effect on motor activity. In the striatum dopamine D] receptors seem to be mainly localized in the strionigral and strioentopeduncular neurons, while dopamine D2 receptors appear to be localized in the GABAeigic striopallidal neurons. In this model, dopamine inhibits the indirect pathway by acting on dopamine D2 receptors and stimulates the direct pathway by acting on dopanaine Dl receptors, which results in a synergistic motor activating effect [1,15] (Fig. 3). We have suggested that specific antagonistic interactions between adenosine A~ and dopamine D1 and between adenosine A2A and dopamine D2 receptors subtypes are responsible for the motor depressant effects of adenosine agonists and the motor activating effects of adenosine antagonists [7-12]. Through these interactions, the stimulation of adenosine A1 and AzA receptors inhibits the effects induced by the stimulation of dopamine D] and

D2 receptors, respectively. Both types of interactions seem to be segregated in the two efferent striatal pathways. In fact, adenosine A2A receptors are mainly localized in the striopallidal neurons and, therefore colocalized with dopamine D2 receptors [13,24]. On the other hand, adenosine At receptors are localized in both subtypes of striatal GABAergic efferent neurons and, therefore, also colocalized with dopamine D1 receptors [12] (Fig. 3). The systemic administration of the adenosine A1 antagonist CPT produced neither motor activation in reserpinized mice nor turning behavior in unilaterally 6-OHdopamine-lesioned rats. These results are in line with other studies [18,21], which show that the A~ adenosine antagonist 8-cyclopentyl-l,3-dipropylxanthine (DPCPX) does not induce any turning behavior in unilateral dopaminedenervated rats. On the other hand, adenosine A2A antagonists seem to be more active than adenosine A~ antagonists in dopamine-depleted animals, since the adenosine A2A antagonist (E)- 1,3-dipropyl-7-methyl-8-(3,4-dimethoxystyril) xanthine (KF17837), but not the adenosine A1 Cerebral Cortex

BS/SC

GP

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! SNc

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~'-

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GLU neuron

Fig. 3. Schemeof the basal ganglia circuitry involvingthe caudate-putamen as the striatal component.The A2A-D2and Aa-D] receptor-receptor interactions seem to be segregatedin the two striatal efferentpathways (see text). BS/SC, Brainstem/spinalcord; DA neuron, dopaminergicneuron; EPN/SNr, entopeduncular nucleus/substantia nigra pars reticulata; GABAneuron, GABAergicneuron; GLU neuron, glutamatergicneuron; GP, globus pallidus; SNc, substantia nigra pars compacta; STN, subthalamic nucleus; THAL, thalamus.

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antagonist 8-(3-oxocyclopentyl)- 1,3-dipropylxanthine (KFM-19), counteracted reserpine-induced catalepsy in mice [19]. However, it has recently been reported that the adenosine A2A antagonist 7-(2-phenylethyl-5amino-2(2-furyl)-pyrazolo(4,3-c)- 1,2,4-triazolo-(1,5-c)pyrimidine (SCH 58261) does not induce turning behavior in unilaterally dopamine-denervated rats [21]. Only non-selective adenosine antagonists, such as caffeine or theophylline, have been reported to induce a clear motor activation in reserpined animals [16,22] or turning behavior contralateral to the dopamine-denervated striaturn in rats [14,17,18]. It has been shown that dopamine antagonists counteract the adenosine antagonist-induced motor activation in dopamine-denervated animals [14,16,17], which suggests that adenosine antagonists are able to potentiate the effects of the endogenous dopamine remaining after dopamine depletion. Therefore, a simultaneous blockade of adenosine AI and A2A receptors, which induces a potentiation of the effects of endogenous dopamine on dopamine D1 and D2 receptors, respectively, seems to be necessary in order to induce a clear motor activation in dopamine-depleted animals. The adenosine A 1 antagonist CPT significantly potentiated the motor stimulating effects of the dopamine D1 agonist SKF 38393 in reserpinized mice and in unilaterally 6-OH-dopamine-lesioned rats. On the other hand, CPT did not potentiate the effects of the dopamine D2 agonist quinpirole with equipotent doses to those of SKF 38393. These results agree with those recently obtained by Pinna et al. [21], which showed that the adenosine A1 antagonist DPCPX induced turning behavior when associated with low ineffective doses of SKF 38393. Furthermore, the same authors have also found that adenosine A2Areceptor blockade potentiates quinpirole- and SKF 38393-induced turning behavior [20,21]. Therefore, adenosine A2A receptor blockade seems to potentiate both dopamine D~ and D2 behavioral effects, while adenosine AI receptor blockade specifically potentiates dopamine D1 receptor effects. According to the model of basal ganglia circuit referred to earlier, and as it was suggested by Pinna et al. [21], the A2Areceptor antagonist-induced potentiation of dopamine Dj receptor effects can be explained by a synergistic effect of the direct pathway (dopamine D1 receptor stimulation induced by the dopamine D1 agonist) and the indirect pathway (potentiation of the effect of endogenous dopamine on dopamine D2 receptors induced by adenosine A2Areceptor blockade) in the output structures of the basal ganglia. The same authors also suggested the involvement of the striatal cholinergic interneurons, which seem to contain excitatory adenosine A2A and dopamine D~ receptors and inhibitory adenosine A1 and dopamine D2 receptors [3,5] (Fig. 3). Since a decrease in acetylcholine neurotransmission potentiates dopamine Dl-mediated responses [6], adenosine A2A receptors localized in ch01inergic interneurons could be involved in the A2A antagonist-induced potentiation of dopamine DI receptor-mediated effects [21].

The failure of the adenosine Ax antagonist to significantly modify the effects of the dopamine D2 agonist could be explained by the more widespread distribution of adenosine Al receptors. On one hand, blockade of the adenosine A1 receptors in the direct pathway (by potentiating the effects of endogenous dopamine on doparnine D1 receptors located in the strionigral and strioentopeduncular neurons) would be expected to produce a synergistic effect of the D2 agonist-mediated effects in the indirect pathway, in the output structures of the basal ganglia. On the other hand, blockade of adenosine Al receptors localized in the striopallidal neurons and the cholinergic interneurons would be expected to oppose to the effects of dopamine D2 receptor stimulation. Furthermore, blockade of inhibitory adenosine A1 receptors localized in the striatal glutamatergic afferents [25] could increase glutamate release, which could also counteract the effects of dopamine Dz receptor stimulation in the striopallidal neurons. In conclusion, the present work shows that an antagonistic interaction between adenosine A1 and dopamine D~ receptors is involved in the motor activating effects of adenosine antagonists. These results underline the potential anti-parkinsonian activity of adenosine A~ antagonists when associated with dopamine D~ agonist treatments or L-dopa treatment. Work supported by a BIOMED 2 program (BMH4CT96-0238), the Italian Research Council (95.01683.CT04), the Swedish Medical Research Council and Marianne and Marcus Wallemberg's Foundation. [1] Alexander, G.E. and Crutcher, M.D., Functional architecture of basal ganglia circuits: neural substxates of parallel processing, Trends Neurosci., 13 (1990) 266-271. [2] And6n, N.-E. and Grabowska-And6n, M., Stimulation of D-1 dopamine receptors reveals direct effects of preferential dopamine autoreceptor agonist B-HT 920 on postsynaptic dopamine receptors, Acta Physiol. Scand., 134 (1988) 285-288. [3] Brown, S.J., James, S., Reddington, M. and Richardson, P.J., Both A~ and A2 purine receptors regulate striatal acetylcholine release, J. Neurochem., 55 (1990) 31-38. [4] Bruns, R.F., Lu, G.H. and Pugsley, T.A., Characterization of the A2 adenosine receptor labeled by [3H]NECA in rat striatal membranes, Mol, Pharmacol., 29 (1986) 331-346. [5] DeBoer, P. and Abercrombie, E.D., Physiological release of striatal acetylcholine in vivo: modulation by D~ and D2 dopamine receptor subtypes, J. Pharmacol. Exp. Ther., 277 (1996) 665-783. [6] Di Chiara, G., Morelli, M. and Consolo, S., Modulatory functions of neurotransmitters in the striatum: acetylcholine/dopamine/ NMDA interactions, Trends Neurosci., 17 (1994) 228-233. [7] Ferr6, S., yon Euler, G., Johansson, B., Fredholm, B.B. and Fuxe, K., Stimulation of high affinity adenosine A-2 receptors decreases the affinity of dopamine D-2 receptors in rat striatal membranes, Proc. Nail. Acad. Sci. USA, 88 (1991) 7238-7241. [8] Ferr6, S., Fuxe, K., von Euler, G., Johansson, B. and Fredholm, B.B., Adenosine-dopamine interactions in the brain, Neuroscience, 51 (1992) 501-512. [9] Ferr6, S., O'Connor, W.T., Fuxe, K. and Ungerstedt, U., The striopallidal neuron: a main locus for adenosine-dopamine interactions in the brain, J. Neurosci., 13 (1993) 5402-5406. [10] Ferr6, S., Popoli, P., Gim6nez-Llort, L., Finnman, U.B., Martfnez,

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