Reversion of muscarinic autoreceptor agonist‐induced acetylcholine decrease and learning impairment by dynorphin A (1–13), an endogenous κ‐opioid receptor agonist

1 We investigated whether carbachol, a muscarinic receptor agonist, induces learning and memory impairment, and if so, dynorphin A (1–13), an endogenous κ‐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 (3×10 −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 nor‐binaltorphimine (5.44 nmol per rat, i.c.v.), a selective κ‐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 κ‐opioid receptors.British Journal of Pharmacology (1998) 123 , 920–926; doi: 10.1038/sj.bjp.0701671