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Cholinergic adaptations to chronic oxotremorine infusion
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 of 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 to 1.0 mg/kg/hr. Clear tolerance was observed in that symptoms such as salivation, lacrimation and muscle tremor decreased or disappeared during the infusion period. Similarly, chronically treated animals exhibited minimal hypothermia or impairment of rotarod performance when challenged with an oxotremorine dose which significantly depressed both of these measures in naive animals. The activities of the enzymes, acetylcholinesterase and choline acetyltransferase, as well as the binding of [3H]-3-quinuclidinyl benzilate in seven brain regions, were assessed. Chronic oxotremorine treatment failed to alter acetyltransferase activity in any of the brain regions. Choline acetyltransferase activity was only marginally decreased in several brain regions. A significant decrease in maximal [3H]-3-quinudidinyl binding was observed in six of the regions examined. 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. These data support the observations of others who noted that chronic muscarinic stimulation results in a decrease in muscarinic receptors, but suggest the importance of mechanisms other than decreased receptor number in early stages of tolerance development.
Insights
Developing tolerance to oxotremorine involves a decrease in muscarinic receptors. However, other mechanisms are important in the early stages of tolerance to this cholinergic agonist.
Area of Science:
- Neuropharmacology
- Receptor Desensitization
- Drug Tolerance
Background:
- Tolerance to cholinergic agonists like oxotremorine is a known phenomenon.
- Previous hypotheses suggested tolerance might stem from reduced muscarinic receptor number or affinity.
Purpose of the Study:
- To investigate the role of muscarinic receptor changes in the development of oxotremorine tolerance.
- To test the hypothesis that decreased muscarinic receptor number or affinity underlies oxotremorine tolerance.
Main Methods:
- C3H mice were chronically infused with oxotremorine (0.03-1.0 mg/kg/hr) via an intravenous catheter.
- Tolerance was assessed by observing behavioral symptoms (salivation, tremor) and physiological responses (hypothermia, rotarod performance).
- Acetylcholinesterase and choline acetyltransferase activities, along with [3H]-3-quinuclidinyl benzilate binding, were measured in seven brain regions.
Main Results:
- Chronic oxotremorine treatment induced significant tolerance, evidenced by reduced symptoms and preserved physiological functions upon challenge.
- A significant decrease in maximal [3H]-3-quinuclidinyl binding was observed in six brain regions, indicating reduced receptor number.
- No alteration in receptor affinity was detected, and enzyme activities remained largely unchanged.
Conclusions:
- Chronic muscarinic stimulation leads to a decrease in muscarinic receptor number, supporting previous findings.
- Tolerance to oxotremorine can occur at doses that do not significantly alter receptor number or enzyme activity.
- These findings suggest that mechanisms beyond decreased receptor number play a crucial role in the early development of tolerance to oxotremorine.