A role for hypocretin/orexin receptor-1 in cue-induced reinstatement of nicotine-seeking behavior

Hypocretin/orexin signaling is critically involved in relapse to drug-seeking behaviors. In this study, we investigated the involvement of the hypocretin system in the reinstatement of nicotine-seeking behavior induced by nicotine-associated cues. Pretreatment with the hypocretin receptor-1 antagonist SB334867, but not with the hypocretin receptor-2 antagonist TCSOX229, attenuated cue-induced reinstatement of nicotine-seeking, which was associated with an activation of hypocretin neurons of the lateral and perifornical hypothalamic areas. In addition, relapse to nicotine-seeking increased the phosphorylation levels of GluR2-Ser880, NR1-Ser890, and p38 MAPK in the nucleus accumbens (NAc), but not in the prefrontal cortex. Notably, phosphorylation levels of NR1-Ser890 and p38 MAPK, but not GluR2-Ser880, were dependent on hypocretin receptor-1 activation. The intra-accumbens infusion of the protein kinase C (PKC) inhibitor NPC-15437 reduced nicotine-seeking behavior elicited by drug-paired cues consistent with the PKC-dependent phosphorylations of GluR2-Ser880 and NR1-Ser890. SB334867 failed to modify cue-induced reinstatement of food-seeking, which did not produce any biochemical changes in the NAc. These data identify hypocretin receptor-1 and PKC signaling as potential targets for the treatment of relapse to nicotine-seeking induced by nicotine-associated cues.This work was supported by the Instituto de Salud Carlos III grants, #PI07/0559, #PI10/00316 and #RD06/001/001 (RTA-RETICS), by the Spanish Ministry of Science and Technology, Consolider-C #SAF2007-64062 and #SAF2011-29864, the Catalan Government (SGR2009-00731), and by the Catalan Institution for Research and Advanced Studies (ICREA Academia program). Ainhoa Plaza-Zabala and África Flores are recipients of a predoctoral fellowship from the Spanish Ministry of Educatio

Methanogens and Methanogenesis in Hypersaline Environments

Methanogenesis is controlled by redox potential and permanency of anaerobic conditions; and in hypersaline environments, the high concentration of terminal electron acceptors, particularly sulfate, is an important controlling factor. This is because sulfate-reducing microbes, compared with methanogens, have a greater affinity for, and energy yield from, competitive substrates like hydrogen and acetate. However, hypersalinity is not an obstacle to methylotrophic methanogenesis; in many cases hypersaline environments have high concentrations of noncompetitive substrates like methylamines, which derive from compatible solutes such as glycine betaine that is synthesized by many microbes inhabiting hypersaline environments. Also, depletion of sulfate, as may occur in deeper sediments, allows increased methanogenesis. On the other hand, increasing salinity requires methanogens to synthesize or take up more compatible solutes at a significant energetic cost. Acetoclastic and hydrogenotrophic methanogens, with their lower energetic yields, are therefore more susceptible than methylotrophic methanogens, which further explains the predominance of methylotrophic methanogens like Methanohalophilus and Methanohalobium spp. in hypersaline environments. There are often deviations from the picture outlined above, which are sometimes difficult to explain. Identifying the role of uncultivated Euryarchaeota in hypersaline environments, elucidating the effects of different ions (which have differential stress effects and potential as electron acceptors), and understanding the effects of salinity on all microbes involved in methane cycling will help us to understand and predict methane production in hypersaline environments. A good demonstration of this is a recent discovery of extremely haloalkaliphilic methanogens living in hypersaline lakes, which utilize the methyl-reducing pathway and form a novel class “Methanonatronarchaeia” in the Euryarchaeota