The peptide nociceptin (also named orphanin FQ) acts in the brain to produce various pharmacological effects, including hyperalgesia and hypolocomotion. The nociceptin receptor uses guanine-nucleotide-binding proteins to mediate the inhibition of adenylyl cyclase, the activation of potassium channels and inhibition of calcium channels. It has been shown using knock-out mice that the nociceptin receptor is not required for regulation of nociceptive responses or locomotion activity, but modulates the auditory function. Here we show that mice lacking the nociceptin receptor possess greater learning ability and have better memory than control mice. Histological analysis revealed the expression of both the nociceptin precursor and the nociceptin receptor in the hippocampus, thought to take part in aspects of learning and memory. Moreover, the receptor-deficient mice showed larger long-term potentiation in the hippocampal CA1 region than control mice, without apparent changes in presynaptic or postsynaptic electrophysiological properties. These results show that the loss of the nociceptin receptor results in a gain-of-function mutation in both the memory process and the long-term potentiation mechanism in CA1, perhaps as a result of altered intracellular signal transduction systems in neurons.

To explore the functional consequences of adult neurogenesis in the mouse olfactory bulb, we investigated plasticity at glutamatergic synapses onto GABAergic interneurons. We found that one subset of excitatory synapses onto adult-born granule cells showed long-term potentiation shortly after their arrival in the bulb. This property faded as the newborn neurons matured. These results indicate that recently generated adult-born olfactory interneurons undergo different experience-dependent synaptic modifications compared with their pre-existing mature neighbors and provide a possible substrate for adult neurogenesis-dependent olfactory learning.

Production of thromboxane (TX) A 2 and PG I 2 /prostacyclin (PGI 2 ) is increased in patients with atherosclerosis. However, their roles in atherogenesis have not been critically defined. To examine this issue, we cross-bred atherosclerosis-prone apoE-deficient mice with mice deficient in either the TXA receptor (TP) or the PGI receptor (IP). Although they showed levels of serum cholesterol and triglyceride similar to those of apoE-deficient mice, apoE -/-TP -/-mice exhibited a significant delay in atherogenesis, and apoE -/-IP -/-mice exhibited a significant acceleration in atherogenesis compared with mice deficient in apoE alone. The plaques in apoE -/-IP -/-mice showed partial endothelial disruption and exhibited enhanced expression of ICAM-1 and decreased expression of platelet endothelial cell adhesion molecule 1 (PECAM-1) in the overlying endothelial cells compared with those of apoE -/-TP -/-mice. Platelet activation with thrombin ex vivo revealed higher and lower sensitivity for surface P-selectin expression in platelets of apoE -/-IP -/-and apoE -/-TP -/-mice, respectively, than in those of apoE -/-mice. Intravital microscopy of the common carotid artery revealed a significantly greater number of leukocytes rolling on the vessel walls in apoE -/-IP -/-mice than in either apoE -/-TP -/-or apoE -/-mice. We conclude that TXA 2 promotes and PGI 2 prevents the initiation and progression of atherogenesis through control of platelet activation and leukocyte-endothelial cell interaction.

Production of thromboxane (TX) A 2 and PG I 2 /prostacyclin (PGI 2 ) is increased in patients with atherosclerosis. However, their roles in atherogenesis have not been critically defined. To examine this issue, we cross-bred atherosclerosis-prone apoE-deficient mice with mice deficient in either the TXA receptor (TP) or the PGI receptor (IP). Although they showed levels of serum cholesterol and triglyceride similar to those of apoE-deficient mice, apoE -/-TP -/-mice exhibited a significant delay in atherogenesis, and apoE -/-IP -/-mice exhibited a significant acceleration in atherogenesis compared with mice deficient in apoE alone. The plaques in apoE -/-IP -/-mice showed partial endothelial disruption and exhibited enhanced expression of ICAM-1 and decreased expression of platelet endothelial cell adhesion molecule 1 (PECAM-1) in the overlying endothelial cells compared with those of apoE -/-TP -/-mice. Platelet activation with thrombin ex vivo revealed higher and lower sensitivity for surface P-selectin expression in platelets of apoE -/-IP -/-and apoE -/-TP -/-mice, respectively, than in those of apoE -/-mice. Intravital microscopy of the common carotid artery revealed a significantly greater number of leukocytes rolling on the vessel walls in apoE -/-IP -/-mice than in either apoE -/-TP -/-or apoE -/-mice. We conclude that TXA 2 promotes and PGI 2 prevents the initiation and progression of atherogenesis through control of platelet activation and leukocyte-endothelial cell interaction.