title: Antagonism of adenosine A2A receptors underlies the behavioural activating effect of caffeine and is associated with reduced expression of messenger RNA for NGFI-A and NGFI-B in caudate-putamen and nucleus accumbens.
abstract: Caffeine, the most widely consumed of all psychostimulant drugs, exerts its action by antagonizing adenosine receptors. To study the arousing properties of caffeine, we injected rats intraperitoneally with vehicle, caffeine (7.5, 15 or 30mg/kg), the selective adenosine A2A receptor antagonist, SCH 58261 (3.75 mg/kg) or the selective adenosine A1 receptor selective antagonist DPCPX (7.5 mg/kg). In a behavioural test it was found that administration of caffeine and SCH 58261 significantly increased locomotion and rearing, whereas DPCPX did not alter locomotion and reduced rearing. After the behavioural session the rats were killed, their brains were cut at several levels along a rostrocaudal axis and in situ hybridization against NGFI-A messenger RNA and NGFI-B messenger RNA was performed. A reduction of NGFI-A messenger RNA was found in several subregions of both caudate putamen and nucleus accumbens in caffeine-treated animals. Similarly, animals that had received SCH 58261 showed significant decreases of NGFI-A messenger RNA in the rostral part of caudate putamen and in the shell part of nucleus accumbens. By contrast, DPCPX treatment caused an increase in the expression of NGFI-A messenger RNA and a smaller increase in NGFI-B messenger RNA in the lateral parts of caudate putamen. In addition, it was found that caffeine, but not SCH 58261 or DPCPX, elevated the expression of NGFI-A and NGFI-B messenger RNA in the cerebral cortex, especially in its parietal part. Thus, these results provide evidence that endogenous adenosine, via adenosine A2A receptors, causes a tonic activation of striatopallidal neurons. By blocking this adenosine effect, caffeine causes behavioural activation.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Svenningsson
authors.forename: G G
authors.initials: GG
authors.lastname: Nomikos
authors.forename: E
authors.initials: E
authors.lastname: Ongini
authors.forename: B B
authors.initials: BB
authors.lastname: Fredholm
mesh_terms: D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D002421:Caudate Nucleus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D017403:In Situ Hybridization; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D009714:Nucleus Accumbens / Q000378:metabolism*; D011699:Putamen / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D018047:Receptors, Purinergic P1; D014157:Transcription Factors; D002110:Caffeine