Interaction of amitriptyline with muscarinic receptor subtypes in the rat brain |
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Authors: | Phyllis Goldman Todd Scranton William S. Messer Jr |
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Affiliation: | Departments of Medicinal and Biological Chemistry and Biology, The University of Toledo, 2801 W. Bancroft St, Toledo, OH 43606, U.S.A. |
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Abstract: | The affinity of amitriptyline for muscarinic receptors in rat brain areas was studied using autoradiographic techniques including image analysis. As shown by competitive inhibition of [3H]-l-quinuclidinyl benzilate binding, amitriptyline was found to be a potent inhibitor of muscarinic receptors throughout the rat brain. Muscarinic receptors in the external layers of the cortex displayed a high affinity for amitriptyline (IC50 = 65.8 ± 2.1 nM), while the hippocampal regions had somewhat lower affinities (e.g. IC50 = 96.3 ± 3.4 nM). Amitriptyline bound with lower affinity in the thalamus and various midbrain regions, such as the paraventricular nucleus of the thalamus and the superior colliculus, which had IC50 values of 112 ± 6.8 and 117 ± 32.6 nM, respectively. Other midbrain regions displayed higher affinities, for example, the substantia nigra had an IC50 value of 62.8 ± 0.9 nM. The data show that amitriptyline binds with high affinity to muscarinic receptors with a modest subtype selectivity that is unlike that of either pirenzepine or AF-DX 116. In addition, amitriptyline at concentrations of 10 nM-1 μM antagonized the oxotremorine-induced inhibition of acetylcholine release in cortical nerve endings, demonstrating activity at M2 autoreceptors. |
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