Prolonged agonist exposure induced imbalance of A1 and A2 receptor-mediated functions in rat brain slices

M. P. Abbracchio, Roberta Brambilla, G. E. Rovati, F. Cattabeni

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Agonist-induced desensitization of A1 and A2 adenosine receptors was studied in brain slices obtained from either rat striatum or cortex, exposed to the adenosine analogue N6-cyclopentyl adenosine (CPA) for selected time periods (15-60 min), and repeatedly washed at the end of agonist exposure. Adenosine receptor function in control and agonist-exposed slices was evaluated by measuring coupling with the cAMP producing system in striatum and with membrane phosphoinositide metabolism in cortex. In rat striatum, exposure to the adenosine analog resulted in a rapid, time- and dose-dependent desensitization of cyclase-linked A1 receptors, as shown by a gradual loss of A1 receptor-mediated inhibition of basal cAMP formation. Binding studies with [3H]cyclo-hexyl-adenosine (CHA) showed nochanges of A1 receptors for the shortest agonist exposure periods utilized (i.e., 15 and 30 min), indeed suggesting an initial uncoupling of receptors from their transduction system. After a 60 min exposure to the adenosine analogue, a significant change of [3H]CHA higher affinity component was instead detected, probably reflecting later agonist-induced receptor changes related to irreversible receptor loss. The initial agonist-induced loss of A1 receptor function was also confirmed in rat cortex, where A1 receptor-mediated modulation of phosphoinositide breakdown was dose-dependently impaired by pre-exposure of slices to the adenosine analogue. A2 receptors seemed resistant to agonist-induced desensitization, at least for the exposure periods utilized. In striatum, changes of A1 receptor function were indeed accompanied by a concomitant increase of A2 receptor mediated stimulation of adenylate cyclase activity, suggesting an 'unmasking' of A2 stimulatory receptors as a consequence of the loss of inhibitory receptors. These results therefore indicate that the over-exposure to adenosine analogues can result in a functional unbalance between A1 and A2 adenosine receptors, which might be at the bases of changes of adenosine neuroprotective activity in brain pathological conditions characterized by an increased release of the nucleoside.

Original languageEnglish
Pages (from-to)364-368
Number of pages5
JournalDrug Development Research
Volume28
Issue number3
StatePublished - Jan 1 1993
Externally publishedYes

Fingerprint

varespladib methyl
Adenosine
Rats
Brain
Adenosine A2 Receptors
Adenosine A1 Receptors
Phosphatidylinositols
Purinergic P1 Receptors
Nucleosides
Adenylyl Cyclases
Metabolism
Modulation
Membranes

Keywords

  • agonist exposed slices
  • agonist-induced desensitization
  • neuroprotection

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Pharmacology

Cite this

Prolonged agonist exposure induced imbalance of A1 and A2 receptor-mediated functions in rat brain slices. / Abbracchio, M. P.; Brambilla, Roberta; Rovati, G. E.; Cattabeni, F.

In: Drug Development Research, Vol. 28, No. 3, 01.01.1993, p. 364-368.

Research output: Contribution to journalArticle

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