Vol. 284, Issue 3, 858-867, March 1998

Effects of U-50,488H on Scopolamine-, Mecamylamine- and Dizocilpine-Induced Learning and Memory Impairment in Rats¹

Masayuki Hiramatsu, Hiroyasu Murasawa, Toshitaka Nabeshima and Tsutomu Kameyama

Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Meijo University, Nagoya 468, Japan and Department of Neuropsychopharmacology and Hospital Pharmacy (T.N.), Nagoya University School of Medicine, Nagoya 466, Japan

The role of kappa opioid receptor agonists in learning and memory is controversial. In the present study, the effects of U-50,488H on scopolamine-, mecamylamine- and dizocilpine-induced learning and memory impairments in rats were investigated. Scopolamine (3.3 µmol/kg s.c.), a muscarinic cholinergic antagonist, and mecamylamine (40 µmol/kg s.c.), a nicotinic cholinergic antagonist, significantly impaired learning and memory in rats in a step-through type passive avoidance test. Administration of U-50,488H (0.17 or 0.51 µmol/kg s.c.) 25 min before the acquisition trial reversed the impairment of learning and memory induced by scopolamine and mecamylamine. Although low doses of scopolamine (0.17 µmol/kg) and mecamylamine (12 µmol/kg) had no effect, concurrent administration of both antagonists induced impairment of learning and memory. Scopolamine significantly increased acetylcholine release in the hippocampus as determined by in vivo brain microdialysis. On the other hand, mecamylamine significantly decreased acetylcholine release. U-50,488H completely blocked the decrease in acetylcholine release induced by mecamylamine, whereas it only partially blocked the increase of acetylcholine induced by scopolamine. On the other hand, an endogenous kappa opioid receptor agonist, dynorphin A (1-13), did not block the increase in acetylcholine release induced by scopolamine. The antagonistic effect of U-50,488H was abolished by pretreatment with nor-binaltorphimine (4.9 nmol/rat i.c.v.), a selective kappa opioid receptor antagonist. U-50,488H did not affect the impairment of learning and memory induced by the blockade of NMDA receptors by dizocilpine ((+)-MK-801). These results suggest that U-50,488H reverses the impairment of learning and memory induced by the blockade of cholinergic transmission and abolishes the decrease of acetylcholine release induced by mecamylamine via the kappa receptor-mediated opioid neuronal system.