The effects of chronic oxotremorine treatment on spatial learning and tolerance development in mice.
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.
Wehner
J M
JM
Institute for Behavioral Genetics, University of Colorado, Boulder 80309.
Upchurch
M
M
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D004361:Drug Tolerance; D005260:Female; D007858:Learning / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D010095:Oxotremorine / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000187:drug effects; D013997:Time Factors
D011976:Receptors, Muscarinic; D010095:Oxotremorine