Alcohol dependence is a major public health challenge in need of new treatments. As alcoholism evolves, stress systems in the brain play an increasing role in motivating continued alcohol use and relapse. We investigated the role of the neurokinin 1 receptor (NK1R), a mediator of behavioral stress responses, in alcohol dependence and treatment. In preclinical studies, mice genetically deficient in NK1R showed a marked decrease in voluntary alcohol consumption and had an increased sensitivity to the sedative effects of alcohol. In a randomized controlled experimental study, we treated recently detoxified alcoholic inpatients with an NK1R antagonist (LY686017; n = 25) or placebo (n = 25). LY686017 suppressed spontaneous alcohol cravings, improved overall well-being, blunted cravings induced by a challenge procedure, and attenuated concomitant cortisol responses. Brain functional magnetic resonance imaging responses to affective stimuli likewise suggested beneficial LY686017 effects. Thus, as assessed by these surrogate markers of efficacy, NK1R antagonism warrants further investigation as a treatment in alcoholism.

IntroductionHematopoietic stem cells (HSCs) have the unique ability to undergo self-renewal and to differentiate into cells belonging to multiple hematopoietic lineages. 1,2 These properties allow stem cells to maintain hematopoiesis throughout the life span of an organism. The knowledge of the behavior of HSCs is limited due to their rarity, difficulty of efficient isolation, and sensitivity to manipulation. 1,2 The self-renewal capacity of several classes of stem cells is thought to be controlled by external signals and intrinsic cellular processes. [1][2][3][4] Over the last 2 decades, a variety of external stimuli (cytokines, matrix proteins) that alter HSC self-renewal have been the subject of intense investigation. Although a number of such external signals that interact with specific receptors on HSC have been identified, the signaling mechanisms that govern HSC self-renewal have eluded investigation. Intrinsic cellular mechanisms that regulate stem cell self-renewal have been explored in a variety of model systems including germline stem cells (GSCs) in several lower species. Drosophila has been a particularly useful model for studying biologic processes that are conserved in higher developmental systems. [5][6][7][8][9][10][11][12] Therefore, in an attempt to define candidate genes that are responsible for human HSC self-renewal, we have explored the expression of genes in humans that have recently been demonstrated to play a role in Drosophila GSC self-renewal.The GSCs provide a continuous source of totipotent cells for the production of gametes needed for fertilization. 8 They are similar to HSCs in their ability to not only self-renew but also to remain capable of generating large numbers of differentiated daughter cells. 8,9 The intracellular mechanisms that serve as the determinants of asymmetric-segregating cell fates of GSCs depend not only on the basic cell cycle machinery but also on a family of recently identified genes, some of which are evolutionarily conserved. 7,9 A group of somatic cells in Drosophila, termed terminal filament cells, which lie distal and immediately adjacent to the GSCs, have been shown to regulate GSC division. 8,10,11 Laser ablation of the terminal filament increases the rate of oogenesis by 40%. 12 Loss of function mutations in a gene found in the terminal filament, termed piwi, leads to a failure of stem cell maintenance 7,10 ; piwi is expressed not only in the terminal filament but also in the germline. Loss of piwi function in the germline, however, is not known to affect GSC division. The protein encoded by piwi is extraordinarily well conserved along the evolutionary tree, being found in both Caenorhabditis elegans and primates. 7 Our laboratory has attempted to determine if such genes were present in primitive hematopoietic cells and if they might play a role in HSC development. We report here the presence of a human homologue of the piwi gene, termed hiwi, in a variety of primitive hematopoietic cells. The hiwi gene represents a candidate gene that may play a ro...