Cholinergic adaptations to chronic oxotremorine infusion

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.