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Anandamides inhibit binding to the muscarinic acetylcholine receptor
by
Lagalwar S, Bordayo EZ, Hoffmann KL,
ABSTRACT
Loss of memory and cholinergic transmission are associated
with both Alzheimer's disease (AD) and marijuana use. The human brain muscarinic
acetylcholine receptor (mAChR), which is involved in memory function and
is inhibited by arachidonic acid, is also inhibited by anandamides. Two
agonists of the cannabinoid receptor derived from arachidonic acid, anandamide
(AEA) and R-methanandamide, inhibit ligand binding to the mAChR. Binding
of the mAChR antagonist [3H]quinuclidinyl benzilate ([3H]QNB) is inhibited
up to 89% by AEA (half-maximal inhibition at 50 microM). Binding of the
more polar antagonist [N-methyl-3H]scopolamine ([3H]NMS) is inhibited by
AEA up to 76% (half-maximal inhibition at 44 microM). R-methanandamide inhibits
more than 90% of both [3H]QNB binding (I50 = 34 microM) and [3H]NMS binding
(I50 = 15 microM) to the mAChR. Both AEA and R-methanandamide stimulate
mAChR binding of the agonist [3H]oxotremorine-M at low concentrations (25-75
microM), but significantly inhibit agonist binding at higher concentrations
(I50 = 150 microM). The cannabinoid antagonist SR141716A did not alter AEA
or R-methanandamide inhibition of [3H]NMS binding to the mAChR, even at
concentrations as high as 1 microM. Further, the cannabinoid agonist WIN
55212-2 does not alter antagonist binding to the mAChR. This demonstrates
that mAChR inhibition by the anandamides is not mediated by the cannabinoid
receptor. Since AEA and R-methanandamide are structurally similar to arachidonic
acid, they may interact with the mAChR in a similar manner to inhibit receptor
function.
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