Studies on new drugs for delayed and progressive learning and memory impairment using kappa-opioid related drugs

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We have reported that kappa-opioid receptor agonist such as dynorphin A improved learning and memory impairment in several animal models with cholinergic dysfunction. Nociceptin is an endogenous ligand for the opioid receptor-like 1 (ORL1) receptor and has some structural homology with the dynorphin A. We have suggested that the ameliorating effect of low doses nociceptin in learning and/or memory impairment may not be mediated by ORL1 receptor. In the hippocampus of ORL1 receptor knockout mouse, expression of kappa_1 opioid receptor mRNA decreased, while mRNA expression of dynorphin and nociceptin precursor protein significantly increased. These changes were presented in beta-amyloid peptide (25-35)-treated mice. The mRNA expression levels of dynorphin precursor protein in the hippocampus 1 week after beta-amyloid peptide (25-35) administration significantly decreased in ORL1 receptor knockout mouse. We used restraint water-immersion stress model and lipopolysaccharide (LPS) to induce delayed and progressive learning and memory impairment to test the effect of dynorphin A and nociceptin. After water-immersion stress, short-term memory was impaired 5 days after stress exposure and the passive avoidance learning was impaired 7 days after stress exposure. These impairments were significantly ameliorated by the antidepressant, desipramine and the acetylcholine esterase inhibitor, tacrine. In addition, they were also ameliorated by antioxidants such as catechin by repeated administration. Further, delayed impairment of learning and memory induced by LPS was also ameliorated by repeated administration of catechin. We need to elucidate the mechanisms of dynorphin A related peptides in these animal models.