The stimulant effects of caffeine on locomotor behaviour in mice are mediated through its blockade of adenosine A_2A receptors

Abstract

1. The locomotor stimulatory effects induced by caffeine (1,3, 7-trimethylxanthine) in rodents have been attributed to antagonism of adenosine A(1) and A(2A) receptors. Little is known about its locomotor depressant effects seen when acutely administered at high doses. The roles of adenosine A(1) and A(2A) receptors in these activities were investigated using a Digiscan actimeter in experiments carried out in mice. Besides caffeine, the A(2A) antagonist SCH 58261 (5-amino-7-(beta-phenylethyl)-2-(8-furyl)pyrazolo[4,3-e]-1,2, 4-triazolo[1,5-c]pyrimidine), the A(1) antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine), the A(1) agonist CPA (N(6)-cyclopentyladenosine) and A(2A) receptor knockout mice were used. 2. Caffeine had a biphasic effect on locomotion of wild-type mice not habituated to the open field, stimulating locomotion at 6.25 - 25 mg kg(-1) i.p. doses, while depressing it at 100 mg kg(-1). In sharp contrast, caffeine dose-dependently decreased locomotion in A(2A) receptor knockout mice over the whole range of tested doses. 3. The depressant effects induced by high doses of caffeine were lost in control CD1 mice habituated to the open field. 4. The A(1) agonist CPA depressed locomotion at 0.3 - 1 mg kg(-1) i.p. doses. 5. The A(1) antagonist DPCPX decreased locomotion of A(2A) receptor knockouts and CD1 mice at 5 mg kg(-1) i.p. and 25 mg kg(-1) i.p. respectively. 6. DPCPX (0.2 - 1 mg kg(-1) i.p.) left unaltered or even reduced the stimulant effect of SCH 58261 (1 - 3 mg kg(-1) i.p.) on CD1 mice. 7. These results suggest therefore that the stimulant effect of low doses of caffeine is mediated by A(2A) receptor blockade while the depressant effect seen at higher doses under some conditions is explained by A(1) receptor blockade.

Adenosinergic Regulation of Striatal Clock Gene Expression and Ethanol Intake During Constant Light

“…Our study supports a role for adenosine in maintaining circadian timing in reward circuitry and for striatal clock genes in regulating alcohol intake and activity. The hyperactive phenotype of ENT1 KO mice is consistent with their low adenosine tone and hyperlocomotion produced by caffeine, the latter mediated by inhibition of A2AR in the NAc (El Yacoubi et al, 2000;Lazarus et al, 2011). In line with increased ethanol intake by A2AR KO mice (Naassila et al, 2002), ENT1 deletion also induces striatal A2AR signaling deficits that increase operant reward responding (Nam et al, 2013).…”

Adenosine A2A Receptor Modulation of Hippocampal CA3-CA1 Synapse Plasticity During Associative Learning in Behaving Mice

“…SCH58261, at doses similar or even higher than that used in the present work, retains A 2A receptor antagonist properties in vivo as it does not mimic centrally mediated actions of selective adenosine A1 receptor antagonists (Connole et al, 2004;Kelsey et al, 2009). Moreover, selective antagonism of A1 receptors does not affect centrally mediated actions of SCH58261 (El Yacoubi et al, 2000). Finally, SCH58261 (i.p.)…”

Adenosine receptor blockade reverses hypophagia and enhances locomotor activity of dopamine-deficient mice

“…In rats treated with caffeine (15 mg͞kg), striatal concentrations peak at 13 M (15). Furthermore, caffeine (25 mg͞kg) administration to A 2A receptor-deficient mice fails to elicit hyperactivity and, in fact, depresses locomotion (16,17), suggesting that the activity-inducing effects of this dose of caffeine are mediated by A 2A receptors.…”

“…But A 1 receptor antagonism with DPCPX was largely ineffective at inducing feeding and locomotion in mutants and did not augment the response to the A 2A antagonist, suggesting that the prophagic and activity-inducing effects of caffeine are mediated by inhibition of postsynaptic A 2A receptors. Indeed, with low caffeine doses (25 mg͞kg or lower) in wild-type animals, it has been hypothesized that A 2A receptors instead of A 1 receptors are preferentially blocked, and hyperlocomotion is induced by net elevation of efficacy of D 2 receptor signaling and depression in G olf activity in striatopallidal neurons (17,23). Higher caffeine doses (75-100 mg͞kg) elicit different responses that involve other pharmacological targets in addition to adenosine receptors, and these higher doses induce striatal immediate-early gene expression (23)(24)(25)(26)(27)(28)(29)(30).…”