Abstract
The mechanism of the therapeutic and prophylactic effects of carbamazepine
(CBZ) in affective psychoses is unknown but may in part be related
to the potent competitive interaction of CBZ with adenosine-binding
sites in the brain. The anticonvulsant and sedative properties of
CBZ are reminiscent of the effects evoked by adenosine-agonists and
contrast sharply with the opposite actions of adenosine-antagonists
like caffeine. However, indirect evidence suggests an antagonist-
rather than an agonist-like activity of CBZ at adenosine-receptors.
We have used various model systems, in which adenosine receptor subtypes
mediate different second messenger-responses, to investigate this-apparent
paradox. CBZ was found to antagonize the A1-receptor-mediated inhibition
of cyclic AMP accumulation in cultured astroblasts and in GH3-cells.
Furthermore, CBZ also inhibits the adenosine-induced increase in
the level of cyclic AMP in cultured astroblasts, which is mediated
by low-affinity A2b-receptors. In contrast, CBZ does not block the
inhibition elicited by adenosine-agonists of the agonist-induced
increased formation of inositolphosphates in human neutrophils, which
is mediated by high-affinity A2a-receptors. The specific antagonism
by CBZ of A1- but not of high-affinity A2a-receptors was further
supported by binding experiments using rat brain membranes. These
results suggest that the paradox of CBZ's antagonistic effects at
adenosine-receptors might be at least partially reconciled by a selective
antagonistic action of CBZ at A1 receptors but not at high-affinity
A2a-receptors.
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