While having no effect on baseline synaptic transmission, the results demonstrate that the selective 5-HT6 agonist, click here WAY-181187, attenuated LTP over a narrow dose range (100-300 nM). The increase in the slope of the field excitatory post

synaptic potential (fEPSP) caused by theta burst stimulation in brain slices treated with the most efficacious dose of WAY-181187 (200 nM) was 80.1+/-4.0% of that observed in controls. This effect was dose-dependently blocked by the selective 5-HT6 antagonist, SB-399885. WAY-181187 also increased the frequency of spontaneous GABA release in area CA1. As assessed by measuring and evaluating spontaneous inhibitory postsynaptic currents (sIPSCs), 200 nM WAY-181187 increased sIPSC frequency by 3.4+/-0.9 Hz. This increase in GABA sIPSCs was prevented by the selective 5-HT6 antagonist SB-399885 (300 nM). Taken together, these results suggest that the 5-HT6 receptor plays a role in the modulation of synaptic plasticity in hippocampal area CA1 and that the regulation of GABAergic interneuron activity may underlie the cognition enhancing effects of 5-HT6 antagonists. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Effective

treatment of chronic pain with morphine is limited by decreases in the drug’s analgesic action with chronic administration (anti nociceptive tolerance). Because opioids are mainstays the of pain management, restoring MK-0518 clinical trial their efficacy has great clinical importance. We have recently reported that formation of peroxynitrite (ONOO(-), PN) in the dorsal horn of the spinal cord plays a critical role in the development of morphine antinociceptive tolerance and have further documented that nitration and enzymatic inactivation of mitochondrial superoxide dismutase (MnSOD) at that site provides a source for this nitroxidative species. We now report for the first time that antinociceptive tolerance in mice is also associated with the inactivation of MnSOD at supraspinal sites. Inactivation of MnSOD led to nitroxidative stress as

evidenced by increased levels of products of oxidative DNA damage and activation of the nuclear factor poly (ADP-ribose) polymerase in whole brain homogenates. Co-administration of morphine with potent Mn porphyrin-based peroxynitrite scavengers, Mn(III) 5,10,15,20-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP(5+)) and Mn(III) 5,10,15,20-tetrakis(N- n-hexylpyridinium-2-yl)porphyrin (MnTnHex-2-PyP(5+)) (1) restored the enzymatic activity of MnSOD, (2) attenuated PN-derived nitroxidative stress, and (3) blocked the development of morphine-induced antinociceptive tolerance. The more lipophilic analogue, MnTnHex-2-PyP(5+) was! able to cross the blood-brain barrier at higher levels than its lipophylic counterpart MnTE-2-pyp(5+) and was about 30-fold more efficacious.