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The effects of chronic oxotremorine treatment on spatial learning and tolerance development in mice
1Institute for Behavioral Genetics, University of Colorado, Boulder 80309.
Abstract:
C57BL mice were treated with 0.5 mg/kg/hr oxotremorine through an implanted subcutaneous cannula for 6 days. Tolerance to oxotremorine was evaluated after treatment by constructing cumulative dose-response curves and measuring body temperature and rotarod performance. At 2 hr after removal, mice exhibited a 15-fold tolerance as measured by body temperature and a 4-fold tolerance as measured by rotarod performance. This tolerance as measured by body temperature was lost by two days after removal from treatment. Immediately after treatment, 3H-QNB binding was reduced in cortex, hippocampus, midbrain, hindbrain, and hypothalamus. Receptors returned to normal within 4 to 8 days after cessation of treatment depending on the brain region. Spatial learning was examined using the Morris water task. Mice that began their training in this task 1 day after they were removed from oxotremorine treatment were impaired in their spatial ability as evidenced by a lack of preference for the trained site during a probe trial. Mice that began their training 2 days after cessation of oxotremorine treatment showed no evidence of impairment in spatial learning. These results suggest that a loss of muscarinic receptors after oxotremorine treatment can be dissociated from tolerance loss and spatial learning deficits.
Insights
Oxotremorine treatment in mice caused tolerance and reduced muscarinic receptors. However, spatial learning deficits resolved before tolerance fully disappeared, suggesting dissociation between receptor loss and cognitive impairment.
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Science
Background:
- Oxotremorine is a muscarinic acetylcholine receptor agonist.
- Tolerance to drug effects and associated neurochemical changes are common.
- Investigating the relationship between receptor changes and behavioral deficits is crucial.
Purpose of the Study:
- To investigate the time course of tolerance to oxotremorine.
- To examine the recovery of muscarinic receptors after oxotremorine treatment.
- To assess the impact of oxotremorine on spatial learning and its recovery.
Main Methods:
- C57BL mice received continuous oxotremorine infusion.
- Tolerance was assessed via body temperature and rotarod performance.
- Muscarinic receptor binding (3H-QNB) and Morris water task were used.
Main Results:
- Significant tolerance to oxotremorine developed after 6 days of treatment.
- Muscarinic receptor binding was reduced across multiple brain regions.
- Spatial learning deficits were observed one day after treatment cessation but resolved by two days.
Conclusions:
- Tolerance to oxotremorine and muscarinic receptor loss are dissociable.
- Spatial learning deficits recover faster than tolerance.
- These findings suggest distinct mechanisms underlying tolerance and cognitive impairment.
