CHOLINERGIC ADAPTATIONS TO CHRONIC OXOTREMORINE INFUSION

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Abstract
The development of tolerance to cholinergic agonists such as oxotremorine is a well established phenomenon. The hypothesis that such tolerance may be explained by a decrease in the number or affinity of muscarinic receptors was tested by chronically treating C3H mice with oxotremorine. Chronic treatment was achieved by continuously infusing oxotremorine via an indwelling i.v. catheter. Doses ranged from 0.03-1.0 mg/kg per h. Clear tolerance was observed in that symptoms such as salivation, lacrimation and muscle tremor decreased or disappeared during the infusion period. Chronically treated animals exhibited minimal hypothermia or impairment of rotarod performance when challenged with an oxotremorine dose, which significantly depressed both measures in naive animals. The activities of acetylcholinesterase and choline acetyltransferase, and the binding of [3H]-3-quinuclidinyl benzilate in 7 brain regions, were assessed. Chronic oxotremorine treatment failed to alter acetylcholinesterase activity in any brain region. Choline acetyltransferase activity was only marginally decreased in several brain regions. A significant decrease in maximal [3H]-3-quinudidinyl binding was observed in 6 regions. No alteration in [3H]-3-quinuclidinyl affinity was detected. Tolerance to oxotremorine was detected at doses which failed to alter choline acetyltransferase activity or receptor number. Chronic muscarinic stimulation decreased muscarinic receptors. Mechanisms other than decreased receptor number in early stages of tolerance development were important.