Reversion of muscarinic autoreceptor agonist-induced acetylcholine decrease and learning impairment by dynorphin A...

1. We investigated whether carbachol, a muscarinic receptor agonist, induces learning and memory impairment, and if so, dynorphin A (1-13), an endogenous kappa-opioid receptor agonist, ameliorates the impairment of learning and memory induced by carbachol, by use of a step-through type passive avoidance task. 2. Carbachol induced a dose-related dual response. Carbachol (1.66 pmol per rat) administered directly into the hippocampus significantly shortened the step-through latency, while lower (0.166 pmol per rat) and higher (16.6 pmol per rat) doses of carbachol did not induce learning or memory impairment. 3. Dynorphin A (1-13) (0.5 nmol per rat, i.c.v.) administered 5 min after carbachol injection significantly reversed carbachol-induced impairment of learning and memory. 4. Perfusion with carbachol (3 x 10(-4) M) significantly decreased acetylcholine release in the hippocampus during perfusion as determined by in vivo brain microdialysis. This decrease in acetylcholine release was suppressed by co-perfusion with a low dose of atropine (10(-7) M). 5. Dynorphin A (1-13) (0.5 nmol per rat, i.c.v.) immediately before carbachol perfusion completely blocked this decrease in extracellular acetylcholine concentration induced by carbachol. 6. These antagonistic effects of dynorphin A (1-13) were abolished by treatment with norbinaltorphimine (5.44 nmol per rat, i.c.v.), a selective kappa-opioid receptor antagonist, 5 min before dynorphin A (1-13) treatment. 7. These results suggest that the neuropeptide dynorphin A (1-13) ameliorates the carbachol-induced impairment of learning and memory, accompanied by attenuation of the reductions in acetylcholine release which may be associated with dysfunction of presynaptic cholinergic neurones via kappa-opioid receptors.