Elsevier

Neuroscience

Volume 80, Issue 4, 11 August 1997, Pages 1187-1207
Neuroscience

Distribution and postnatal ontogeny of adenosine A2A receptors in rat brain: comparison with dopamine receptors

https://doi.org/10.1016/S0306-4522(97)00143-7Get rights and content

Abstract

In adult rat brain, adenosine A2A receptors and dopamine D2 receptors are known to be located on the same cells where they interact in an antagonistic manner. In the present study we wanted to examine when this situation develops and compared the postnatal ontogeny of the binding of the adenosine A2A receptor agonist [3H]CGS 21680, the binding of the dopamine D1 receptor antagonist [3H]SCH 23390 and the dopamine D2 receptor antagonist [3H]raclopride.

All three radioligands bound to the striatum at birth and this binding increased several-fold during the postnatal period. [3H]SCH 23390 binding developed first (mostly during the first week), followed by [3H]raclopride binding (first to third week) and [3H]CGS 21680 binding (only during second and third week). For all three radioligands the binding tended to decrease between 21 days and adulthood. This occurred earlier and was more pronounced in the globus pallidus than in the other examined structures. The increase in [3H]CGS 21680 binding from newborn to adult was mainly due to four-fold increase in the number of binding sites. The pharmacology of [3H]CGS 21680 binding to caudate–putamen was similar in newborn, one-week-old and adult animals, and was indicative of A2A receptors. The binding was inhibited by guanylyl imidodiphosphate at all ages, indicating that A2A receptors are G-protein-coupled already at birth. In contrast to the large increase in [3H]CGS 21680 binding, there was a decrease in the levels of A2A messenger RNA during the postnatal period in the caudate–putamen. In cerebral cortex [3H]CGS 21680 bound to a different site than the A2A receptor. From birth to adulthood cortical binding of [3H]CGS 21680 increased four-fold and that of the adenosine A1 agonist [3H]cyclohexyladenosine 19-fold. During early postnatal development [3H]SCH 23390 binding was higher in deep than in superficial cortical layers, but this difference disappeared in adult animals. There was binding of both [3H]CGS 21680 and [3H]cyclohexyladenosine to the olfactory bulb, suggesting a role of the two adenosine receptors in processing of olfactory information. [3H]CGS 21680 binding was present in the external plexiform layer and glomerular layer, and increased during development, but the density of binding sites was about one tenth of that seen in caudate–putamen. [3H]cyclohexyladenosine showed a very different labelling pattern, resembling that observed with [3H]SCH 23390.

Postnatal changes in adenosine receptors may explain age-dependent differences in stimulatory caffeine effects and endogenous protection against seizures. Since A2A receptors show a co-distribution with D2 receptors throughout development, caffeine may partly exert such actions by regulating the activity of D2 receptor-containing striatopallidal neurons

Section snippets

Animals

These studies, which were approved by the regional animal ethics committee, used Sprague–Dawley rats (B&K, Sollentuna, Sweden. The number of animals at each age group was (figures within parenthesis): Newborn (19 animals), two-day-old (6), five-day-old (6), seven-day-old (15), 10-day-old (6), 15-day-old (5), 21-day-old (5) and adult (three- to four-months-old; 21 animals). Three to five animals of each age from at least two separate litters were used for each experiment, unless specifically

[3H]CGS 21680, [3H]SCH 23390 and [3H]raclopride binding in adults

As seen in Fig. 1 and Fig. 2, and in agreement with previous studies, A2A receptors, D1 receptors and D2 receptors were enriched in caudate–putamen, accumbens nucleus, olfactory tubercle and globus pallidus. However, at all ages there was also a lower level of binding of [3H]CGS 21680 to many of the brain's gray matter structures including the cerebral cortex and hippocampus, confirming recent results.48, 49There was also binding to the olfactory bulb (see below). In agreement with previous

Usefulness of the radioligands used

In the present study we have used radioligands reported to be quite selective for D1, D2, A2A, and A1 receptors, respectively. Although the binding of [3H]CGS 21680 to the basal ganglia structures in focus here appear to represent classical A2A receptors (as evidenced by the pharmacology), we have previously found that in cortical areas [3H]CGS 21680 appears to bind to a site different from the A2A receptor present in the striatum.14, 48, 49The present results show that these low-affinity

Conclusions

In the areas examined, A1, A2A, D1 and D2 receptors increase markedly during the first weeks of extrauterine life, as reported for many receptors.[41]We have found that quantitative receptor autoradiography is a very useful technique to study ontogeny of brain receptors, since it gives highly reproducible values for small regions in the developing animal that are difficult to dissect out and from which only minute amounts of membrane protein can be prepared. Autoradiography and regional

Acknowledgements

This study was supported by the Swedish Medical Research Council (proj. no. 2553), Magnus Bergvall's and Lars Hierta's foundations, the Swedish Society for Medical Research, the Institute for Scientific Information on Coffee, Astra Arcus, a BIOMED 2 project (BM4-CT96-0238), and Karolinska Institutet. B.J. was a recipient of a Swedish MRC scholarship. V.G. was supported by the European Science Foundation, an ENP/European Research Grant and grants from the Swedish Institute and the Karolinska

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    Present address: Department of Experimental Pharmacology, Institute of Physiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria.

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