No abstract

Drugs targeting the histamine H 3 receptor (H 3 R) are suggested to be beneficial for the treatment of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. The H 3 R activates G i/o -proteins to inhibit adenylyl cyclase activity and modulates phospholipase A 2 and MAPK activity. Herein we show that, in transfected SK-N-MC cells, the H 3 R modulates the activity of the Akt/Glycogen synthase kinase 3b (GSK-3b) axis both in a constitutive and agonist-dependent fashion. H 3 R stimulation with the H 3 R agonist immepip induces the phosphorylation of both Ser473 and Thr308 on Akt, a serine/threonine kinase that is important for neuronal development and function. The H 3 R-mediated activation of Akt can be inhibited by the H 3 R inverse agonist thioperamide, and by Wortmannin, LY294002 and PTX, suggesting the observed Akt activation occurs via a G i/o -mediated activation of phosphoinositide-3-kinase. H 3 R activation also results in the phosphorylation of Ser9 on GSK-3b, which acts downstream of Akt and has a prominent role in brain function. In addition, we show the H 3 Rmediated phosphorylation of Akt at Ser473 to occur in primary rat cortical neurons and in rat brain slices. The discovery of this signaling property of the H 3 R adds new understanding to the roles of histamine and the H 3 R in brain function and pathology.

Consolidation refers to item stabilization in long-term memory. Retrieval renders a consolidated memory sensitive, and a "reconsolidation" process has been hypothesized to keep the original memory persistent. Some authors could not detect this phenomenon. Here we show that retrieved contextual fear memory is vulnerable to amnesic treatments and that the amygdala is critically involved. Cholinergic and histaminergic systems seem to modulate only consolidation, whereas cannabinoids are involved in both consolidation and reactivation. The lability of retrieved memory affords opportunities to treat disorders such as phobias, post-traumatic stress, or chronic pain, and these results help searching for appropriate therapeutic targets.

The aim of this study was to better understand the role of the endothelin-1 (ET-1) system in the process of controlling the corpora lutea (CL) life span in rabbits. ET-1 (10 microg iv) administration at d 9 and 12 of pseudopregnancy induced a functional luteolysis within 24 h of injection, but it was ineffective at both d 4 and 6. Pretreatments with Bosentan, a dual ET(A)/ET(B) receptor antagonist, or cyclooxygenase (COX) inhibitor blocked the luteolytic action of ET-1 but not that induced by prostaglandin F2alpha (PGF2alpha). In CL cultured in vitro, ET-1 increased (P

Stimulation of histamine H 3 receptors (H 3 R) activates G i/oproteins that inhibit adenylyl cyclase and triggers MAPK and phospholipase A 2 . In a previous study, we showed that H 3 Rmediated phosphorylation of Akt at Ser473 occurs in primary cultures of rat cortical neurons, but neither the downstream targets nor the function of such activation were explored. In this report we address these questions. Western blotting experiments showed that H 3 R-mediated activation of Akt in cultured rat cortical neurons was inhibited by LY 294004 and U0126, suggesting that it depends on phosphoinositide-3-kinase and mitogen-activated protein kinase kinase. H 3 R activation phosphorylated, hence inactivated, the Akt downstream effector glycogen synthase kinase-3b, increased the expression of the antiapoptotic protein Bcl-2 and protected cultured rat and mouse cortical neurons from neurotoxic insults in a dose-dependent manner. All these effects were inhibited by the H 3 R antagonist inverse/agonist thioperamide. Mouse cortical cells expressed H 3 R as revealed by immunostaining experiments, and stimulation of H 3 R phoshorylated Akt and decreased caspase 3 activity. Hence, we uncovered a yet unexplored action of the H 3 R that may help understand the impact of H 3 R signaling in the CNS.