Research report
Cross-sensitization between the motor activating effects of bromocriptine and caffeine: role of adenosine A2A receptors

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Abstract

The acute motor response to caffeine was studied in rats repeatedly treated with vehicle or the dopamine D2 agonist bromocriptine either in a novel cage or in the home cage. Rats receiving bromocriptine (5 mg/kg i.p.) in a novel cage were sensitized to the motor stimulating effects of bromocriptine itself and showed cross-sensitization to the acute administration of low (10 mg/kg s.c.) but not high (25 mg/kg s.c.) doses of caffeine, no matter if the novel cage was identical or different from the test cage. In contrast, caffeine (10 mg/kg i.p.) administered to rats which had received bromocriptine (5 mg/kg i.p.) in the home cage and which showed no sign of a sensitized response to bromocriptine, failed to show an increased locomotor and stereotyped response as compared to vehicle pretreated rats. Similarly to caffeine, the selective adenosine A2A antagonist SCH 58261 (3 mg/kg i.p.) showed an increased motor response in bromocriptine sensitized rats. The sensitized response to caffeine or SCH 58261 did not appear to be due to an higher basal motor activity of bromocriptine sensitized rats since acute administration of vehicle induced a similar motor response in bromocriptine and vehicle pretreated rats. Dopamine D2 and adenosine A2A receptors are colocalized in striatal efferent neurons where they control in an opposite direction motor behavior. The results of the present study showed that changes in the sensitivity of D2 receptors influenced the sensitivity of the adenosine antagonist caffeine through an action on A2A receptors. D2 and A2A receptors, therefore, not only acutely interact in the mediation of motor behavior but long-term modification of the D2 receptors, such as sensitization, affected the response of adenosine A2A receptors.

Introduction

Caffeine produces psychomotor stimulant effects by enhancing locomotor activity and schedule controlled behavior [5], [12], [16], [18], [19], [23], [25], [35], [40]. To induce these effects, caffeine largely interacts with the dopamine system as shown by the antagonism of caffeine-induced motor behavior by dopamine receptor antagonists [9], [13], [14], [27] or by the potentiation of cocaine discriminative stimulus and by the increase in cocaine self-administration by caffeine [16], [18], [35], [40].

The actions of caffeine are mediated through different mechanisms, however, the only mechanism which is affected by doses of caffeine relevant to normal human consumption is the antagonism of adenosine A1 and A2 receptors [12].

The motor stimulant effects of caffeine appear to be related to an action on the high affinity adenosine A2A receptor since the A2A antagonists CGS 15943 and SCH 58261 stimulate motor behavior while the A1 antagonist DPCPX has been shown to produce motor stimulation only in one study by Popoli et al. [32], whereas other reports did not show any stimulant property [17], [22], [31], [39].

Adenosine A2A receptors are concentrated in areas receiving a rich dopamine innervation as the dorsal and ventral striatum and tuberculum olfactorium [24], [38]. In the striatum, A2A receptors are colocalized with dopamine D2 receptors in medium-sized spiny GABAergic neurons projecting to the globus pallidus and expressing enkephalin [11], [36]. D2 and A2A receptors functionally interact at the biochemical level as demonstrated by the decrease in D2 receptor affinity after A2A receptors activation and by the interaction, in an opposite direction, on cAMP formation [7], [10].

Our group and a recent study by Casas et al. [6] have shown that in unilaterally 6-hydroxydopamine lesioned rats the contralateral rotation induced by caffeine is strongly increased by previous or concomitant exposures to dopamine receptor agonists [8], [27]. Moreover, whereas the effects on caffeine contralateral rotation induced by a previous exposure to a dopamine D1 receptor agonist are context independent, those induced by stimulation of D2 receptors are strongly influenced by the context where the D2 agonist and caffeine are administered [8]. These studies indicate that adenosine and dopamine receptors not only acutely interact in the mediation of motor behavior [9], [14], [29], [31], but suggest that a previous stimulation of dopamine receptors produces long-term modification which alter the responses induced by drugs acting at the adenosine receptor level.

Repeated administrations of psychomotor stimulants or dopamine receptor agonists to rodents increase their motor activating effects progressively. This phenomenon denominated behavioral sensitization produces long-term modifications and play an important role in drug abuse [26], [33], [37].

The acute pharmacological interaction in the mediation of motor behavior, between dopamine agonists and adenosine receptor antagonists, has been previously characterized [9], [13], [15], [31]. In contrast, how the effect of neuronal adaptations, such as sensitization, involving the dopamine system can influence the motor stimulant effects of the adenosine antagonist caffeine have not been evaluated.

To test whether the presence of a sensitization to dopamine receptor agonists can alter the motor responses induced by caffeine, the motor behavior induced by caffeine in rats previously exposed to repeated administrations of the dopamine D2 receptor agonist bromocriptine has been evaluated. As reported by Hoffman and Wise [20], [21], selective stimulation of D2 receptors sensitizes rats to subsequent injections just as do psychostimulants. In order to evaluate the role of conditioning in the motor responses obtained, administration of bromocriptine was performed in the home cage or in a novel cage which was either similar (paired group) or different (unpaired group) from the cage where rats received caffeine.

In light of the reports showing that the motor responses induced by caffeine are mediated by a blockade of A2A adenosine receptors [17], [22], [39], the motor effects elicited by selective blockade of A2A receptors with the selective A2A receptor antagonist SCH 58261 [41] in bromocriptine sensitized rats have also been studied.

Section snippets

Subjects

Experiments were conducted in adult male Sprague–Dawley rats, weighing 200–250 g at the beginning of the experiments. Some of the rats were housed individually (home cage experiments), the rest of them were housed six per cage.

Animal room was maintained on a 12 light/dark cycle (lights on at 08:00 h). Food and water were freely available except during experimental session. All tests were conducted between 13:00 and 18:00 h.

Measurement of locomotor and stereotyped activity

Measurement of motility was performed in a quiet isolated room. Rats

Induction of sensitization to bromocriptine

Repeated administration of bromocriptine (5 mg/kg i.p.) to rats paired or unpaired with the test cage produced a progressively larger increase in locomotor and total motor activity from the first to the sixth injection. Locomotor activity (paired group): F(5,240)=9.96, P<0.001; total motor activity (paired group): F(5,240)=8.22, P<0.001 (Fig. 1A). Locomotor activity (unpaired group): F(5,90)=8.53, P<0.001; total motor activity (unpaired group): F(5,90)=7.34, P<0.001 (Fig. 1B). Locomotor and

Discussion

Repeated administration of bromocriptine in environmental conditions which induce a sensitized response to bromocriptine itself, produced a greater enhancement of caffeine-induced motor activity as compared to rats repeatedly treated with the vehicle. These results underlie the importance of the interaction between the adenosinergic and dopaminergic systems not only on the acute mediation of motor behavior, as previously shown, [9], [14], [29], [31] but also in long-term effects as in

Acknowledgements

The authors wish to thank Dr Ennio Ongini from Schering-Plough, Milano, Italy for providing SCH 58261 and Mrs Adelaide Marchioni for typing the manuscript.

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