Behavioural Brain Research 114 (2000) 97 – 105 Research report Cross-sensitization between the motor activating effects of bromocriptine and caffeine: role of adenosine A 2A receptors Sandro Fenu, Omar Cauli, Micaela Morelli * Department of Toxicology, Uniersity of Cagliari, Viale A. Diaz 182, 09126 Cagliari, Italy Received 29 December 1999; received in revised form 20 March 2000; accepted 20 March 2000 Abstract The acute motor response to caffeine was studied in rats repeatedly treated with vehicle or the dopamine D 2 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 A 2A 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 D 2 and adenosine A 2A 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 D 2 receptors influenced the sensitivity of the adenosine antagonist caffeine through an action on A 2A receptors. D 2 and A 2A receptors, therefore, not only acutely interact in the mediation of motor behavior but long-term modification of the D 2 receptors, such as sensitization, affected the response of adenosine A 2A receptors. © 2000 Elsevier Science B.V. All rights reserved. Keywords: Bromocriptine; Caffeine; A 2A receptors; D2 receptors; Sensitization; Adenosine www.elsevier.com/locate/bbr 1. 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 discrimi- native stimulus and by the increase in cocaine self-ad- ministration by caffeine [16,18,35,40]. The actions of caffeine are mediated through differ- ent mechanisms, however, the only mechanism which is affected by doses of caffeine relevant to normal human consumption is the antagonism of adenosine A 1 and A 2 receptors [12]. The motor stimulant effects of caffeine appear to be related to an action on the high affinity adenosine A 2A receptor since the A 2A antagonists CGS 15943 and SCH 58261 stimulate motor behavior while the A 1 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 A 2A receptors are concentrated in areas receiving a rich dopamine innervation as the dorsal and ventral striatum and tuberculum olfactorium [24,38]. In * Corresponding author. Tel.: +39-70-303819; fax: +39-70- 300740. E-mail address: micmor@tin.it (M. Morelli). 0166-4328/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved. PII:S0166-4328(00)00190-X