title: Characterisation of central adenosine A(1) receptors and adenosine transporters in mice lacking the adenosine A(2a) receptor.
abstract: The present study was designed to assess whether adenosine A(2a) receptor knockout mice exhibit altered purine utilisation in brain nuclei. Specifically, the properties of adenosine transporters and adenosine A(1) receptors were characterised in brain membranes and on slide-mounted sections. The B(MAX) for [(3)H]nitrobenzylthioinosine ([(3)H]NBTI) binding (adenosine transporter density) was significantly reduced in brainstem membranes of homozygotes (560+/-52 fmol/mg protein, n=5, P<0.05, Kruskal-Wallis ANOVA) compared to wildtype (1239+/-213 fmol/mg protein) and heterozygous mice (1300+/-558 fmol/mg protein). Quantitative autoradiography data indicated that [(3)H]NBTI binding in the medulla oblongata of heterozygous mice was seen to decrease significantly (P<0.05) in the subpostremal nucleus tractus solitarius (NTS), medial NTS, inferior olive and area postrema (AP). On the other hand, in the homozygous mice a decrease was seen in the medial NTS and AP. In the pons, [(3)H]1, 3-dipropyl-8-cyclopentylxanthine ([(3)H]DPCPX) (adenosine A(1) receptor density) binding increased significantly (P<0.05, Kruskal-Wallis ANOVA) in the lateral parabrachial nucleus, caudal pontine reticular nucleus and locus coeruleus of homozygotes compared to wildtype. In higher brain centres, [(3)H]NBTI binding was reduced in the paraventricular thalamic nucleus of both heterozygous and homozygous mice, whereas [(3)H]DPCPX binding was reduced in the hippocampus and lateral hypothalamus of heterozygotes. In homozygotes, [(3)H]DPCPX binding in the hippocampus increased compared to wildtype mice. The present study indicates that deletion of the A(2a) receptor may have contributed to region-specific compensatory changes in purine utilisation in brain nuclei associated with autonomic, neuroendocrine and behavioural regulation.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Monash University, Wellington Rd, Clayton, Victoria 3800, Australia.
authors.forename: B J
authors.initials: BJ
authors.lastname: Snell
authors.forename: J L
authors.initials: JL
authors.lastname: Short
authors.forename: J
authors.initials: J
authors.lastname: Drago
authors.forename: C
authors.initials: C
authors.lastname: Ledent
authors.forename: A J
authors.initials: AJ
authors.lastname: Lawrence
mesh_terms: D000345:Affinity Labels / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D001923:Brain Chemistry / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism* / Q000648:ultrastructure; D005838:Genotype; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011869:Radioligand Assay; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014316:Tritium; D014970:Xanthines / Q000494:pharmacology
chemical_list: D000345:Affinity Labels; D002352:Carrier Proteins; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D014970:Xanthines; D014316:Tritium; D013868:Thioinosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; C001789:4-nitrobenzylthioinosine