[Possible mechanisms in latent learning formation investigated by using mutant mice].

We examined possible mechanisms in the development of latent learning by methods of behavioral pharmacology and confirmed them by using mutant mice. Mice that received dopamine agonists, a noradrenergic neurotoxin or a traumatic brain injury showed impairment of latent learning. This impairment was suggested to be mediated by imbalance of dopaminergic and noradrenergic systems since the impairment was attenuated by a noradrenaline uptake inhibitor or a dopamine-D2 antagonist. The heterozygous mice for the tyrosine hydroxylase (TH) gene and for the cyclic AMP (cAMP) response element binding protein (CREB) binding protein (CBP) gene showed impairment of latent learning in the water finding task. The spatial learning and hippocampal long-term potentiation (LTP) were normal in both the mutants. TH heterozygous mice showed a reduction of high K(+)-evoked noradrenaline release in the frontal cortex by the microdialysis technique and a reduction of cAMP of the brain cAMP content. The central noradrenergic systems and/or cAMP signal pathways play an important role in latent learning, but not spatial memory. In contrast with TH and CBP mutant mice, nociceptin-knockout mice showed an enhanced retention of latent learning in the water finding task, greater learning ability in the water maze task and larger LTP than wild-type mice. Such mice showed hyperfunction of dopaminergic systems in the cortex. Nociceptin itself induced latent learning impairment in wild-type mice. These results suggest that the nociceptin system seems to play negative roles in learning and memory. In conclusion, the results of mutant mice further supported our previous results of behavioral pharmacology and suggest that the alternation of catecholamine biosynthesis and cAMP signal pathways may play a key role in development of latent learning. They further suggest that the expression of genes mediated by phosphorylated CREB may be involved in the development of latent learning.