PT  - JOURNAL ARTICLE
AU  - FREDERICK J. EHLERT
AU  - NORIO KOKKA
AU  - ALAN S. FAIRHURST
TI  - Altered [<sup>3</sup>H]Quinuclidinyl Benzilate Binding in the Striatum of Rats following Chronic Cholinesterase Inhibition with Diisopropylfluorophosphate
DP  - 1980 Jan 01
TA  - Molecular Pharmacology
PG  - 24--30
VI  - 17
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/17/1/24.short
4100  - http://molpharm.aspetjournals.org/content/17/1/24.full
SO  - Mol Pharmacol1980 Jan 01; 17
AB  - Chronic administration of diisopropylfluorophosphate to rats at a dose regimen producing 90% inhibition of striatal cholinesterase caused a significant decrease in the density of [3H]quinuclidinyl benzilate binding sites in homogenates of the striatum. The concentration of binding sites decreased from 1.39 ± 0.06 in controls to 0.82 ± 0.02 pmol/mg protein in diisopropylfluorophosphate-treated rats, and the half-time for the loss of binding sites was approximately 1.6 days. This decrease in [3H]quinuclidinyl benzilate binding was not due to a direct effect of diisopropylfluorophosphate on muscarinic receptors since no inhibition of binding was produced by high concentrations of diisopropylfluorophosphate when added in vitro. An increase in the Ki for inhibition of [3H]quinuclidinyl benzilate binding by various nonlabeled cholinergic ligands was observed in chronic diisopropylfluorophosphate-treated rats, indicating that the affinity of the muscarinic receptors in the striatum had decreased. Following diisopropylfluorophosphate treatment, muscarinic receptors displayed a greater decrease in affinity to muscarinic agonists than to antagonists. Scatchard analysis of oxotremorine inhibition of [3H]quinuclidinyl benzilate binding showed both high (KH = 0.01 ± 0.002 µM) and low (KL = 0.86 ± 0.18 µM) affinity binding sites in relative densities of 26 and 74%, respectively. Chronic administration of diisopropylfluorophosphate produced an increase of KH to 0.037 ± 0.008 µM, indicating a decrease in affinity but had no significant effects on KL or on the relative densities of the two sites. Similar results were obtained for acetylcholine and pilocarpine. In contrast, Scatchard analysis of the atropine inhibition of [3H]quinuclidinyl benzilate binding showed a single class of antagonist binding sites. These decreases in affinity and density of muscarinic receptors in the striatum following chronic cholinesterase inhibition demonstrate that the tolerance to diisopropylfluorophosphate is, in part, a receptor mediated phenomenon.