Behavioral effects of intrastriatal caffeine mediated by adenosinergic modulation of dopamine

Although caffeine is generally classified as a psychomotor stimulant, the neurotransmitter systems mediating its effect on behavior have not yet been established. Mounting evidence suggests possible involvement of adenosinergic and/or dopaminergic (DA) systems. To evaluate these possibilities, four experiments examined circling behavior in rats following unilateral intrastriatal microinjections of: 1) caffeine alone; 2) the adenosine agonist, 2-chloroadenosine (2-CADO) alone; 3) caffeine with 2-CADO pretreatment; and 4) caffeine with pretreatment of the DA receptor antagonist, cis-flupenthixol. Each experiment consisted of seven test sessions; the first and seventh were preceded by no treatment, the second and sixth by control microinjections (saline or cis-flupenthixol) and the third, fourth and fifth by drug microinjections. Results showed that 10.0 and 20.0 but not 1.0 micrograms of caffeine produced a significant contraversive bias in circling behavior, while 2.0 and 5.0 but not 1.0 microgram doses of 2-CADO produced significant ipsiversive circling. Rats pretreated with central 2-CADO or cis-flupenthixol (in doses that did not influence circling bias when administered alone) prior to caffeine (10.0 micrograms) failed to exhibit a contraversive bias. Taken together, the present studies provide compelling support for the suggestion that the motor effects of intrastriatal caffeine are mediated by the antagonism of endogenous adenosine which, in turn, functionally increases DA.