Heather M. Haughey, Ph.D. - US grants

DESCRIPTION: (Provided by Applicant) The overall goal of this post-doctoral fellowship is to elucidate the signaling mechanisms by which dopamine (DA) D2 receptor (D2R) activation modulates dopamine transporter (DAT) function and expression. The proposed experiments will test the hypotheses that (1) the biochemical mechanisms underlying the D2R mediated increase in DAT function and cell surface expression is through G-beta gamma-subunit interactions with the mitogen activated protein kinase (MAPK) pathway, and (2) the effects of D2R stimulation on DAT in postnatal DA neuronal cultures will be similar to those observed in oocytes. D2R activation causes a rapid increase in the velocity of DA uptake and the number of cell surface DATs in Xenopus oocytes co-expressing human (h) D2Rs and DATs. First, we will determine the role of the G-beta gamma subunit in the D2R-mediated effects on hDAT function ([3H]DA uptake, hDAT-associated currents) and expression ([3H]WIN 35428 binding) in oocytes. Next, we will examine the involvement of the MAPK pathway in these D2R-mediated effects on hDAT function and expression in oocytes. Finally, we will characterize the effects of D2R stimulation on DAT function in postnatal DA neuronal cultures. Once established, this neuronal culture system will be very valuable for further studies elucidating the mechanisms by which drugs of abuse alter DAT regulation. These experiments will enhance our understanding of the signaling mechanisms mediating D2R regulation of DAT, the target of important drugs of abuse and a critical component responsible for modulating dopaminergic synaptic neurotransmission.

DESCRIPTION (provided by applicant): Candidate. The candidate, Heather M. Haughey, Ph.D., is a research associate with extensive experience in both neurochemical and molecular, approaches to the study of alcohol dependence but little experience with clinical approaches and research with humans. Her immediate career goal is to acquire the research and professional skills necessary for achieving her long-term goal of developing an independent, extramurally-funded translational research that spans molecular, cellular, and behavioral approaches to the study of alcohol dependence in humans. A five-year Career Development Plan will provide the candidate with the multi-disciplinary skills required to ultimately lead an independent and highly productive research program in alcohol dependence. Career Development Plan. This plan has been carefully devised to satisfy specific career development needs in the following major areas: (1) clinical research methods in alcohol dependence; (2) instrumentation and analysis of genotyping single nucleotide polymorphisms; and (3) quantitative skills and biostatistics. Formal training in these highly specialized areas will be achieved through an intensive curriculum of seminars, classes, tutorials, extramural didactics, and research studies. Environment. The environment for Dr. Haughey's proposed training is outstanding. The primary sponsor, Dr. Kent Hutchison, is a well-established extramurally funded scientist with an excellent record of successful mentoring and a decade of experience in human alcohol research; the co-sponsors and consulting mentors provide excellent guidance in specific components of the research plan, including molecular biology, genetics and statistical methodologies. Research. Three specific aims are proposed which seek to test the overall global hypothesis that polymorphisms within the NET gene that alter function/expression contribute to the development of alcoholism. We propose 1) to determine the functional significance of NET coding SNPs at a cellular level; 2) to identify and characterize gene-bypharmacotherapy interaction(s) on intermediate laboratory based phenotypes (e.g., cue elicited craving, sensitivity to the acute effects of alcohol); and 3) to conduct secondary analyses of existing datasets (e.g., WHO/ISBRA) to determine whether variation in the NET gene is associated with the presence of alcohol dependence and/or depression. The findings from these studies will offer insight into the genetic determinants influencing the development of alcoholism and may guide the development of more effective pharmacotherapies for these devastating brain disorders.

DESCRIPTION (provided by applicant): One of NIDA's highest priorities for funding is the development of effective pharmacotherapies for substance related disorders. In response to RFA-DA-09-005, soliciting pilot clinical/human studies of interventions that specifically target mechanisms known to play an important role in the etiology of drug addiction, we propose to perform a pilot clinical trial of medication to target a neuromodulator of stress in the CNS, the neurokinin 1 (NK1) receptor system. Based on inferences from recent reports in the scientific literature, the NK1 receptor system is a new potential therapeutic treatment strategy for the cessation of cannabis use in individuals who also smoke tobacco. We hypothesize that the NK1 receptor antagonist, aprepitant, will be efficacious at reducing the withdrawal symptoms, cue craving, and reinforcement value for both cannabis and tobacco resulting from the cessation of either or both drugs. We will assess this hypothesis in the context of a carefully controlled human laboratory study in which subjects (N=108) will be randomized in a 3 x 3 factorial design to one of 3 behavioral conditions: a) withdrawn from both substances, b) withdrawn from tobacco only, or c) withdrawn from cannabis only, and to receive one of 3 medication dose conditions: placebo, low-dose aprepitant (80 mg/day), or high-dose aprepitant (160 mg/day). Medication will be administered for 5 days, followed by a cue challenge, choice procedure, and then a consequence (i.e., oral cannabis or a cigarette or money) also on day 5. The scientific significance is that NK1 receptor antagonists promise to be an important new target for the development of therapeutic medications for treating heavy cannabis smokers. The results of our human laboratory study will lay the foundation for subsequent clinical trials of aprepitant for the treatment of cannabis dependence among individuals who smoke tobacco for the alleviation of either or both concurrent disorders. PUBLIC HEALTH RELEVANCE: The scientific significance of our study is that NK1 receptor antagonists promise to be an important new target for the development of putative therapeutic medications for treating heavy cannabis users who also smoke tobacco. The results of our human laboratory study will lay the foundation for subsequent clinical trials of aprepitant for the treatment of cannabis dependence among individuals who smoke tobacco for the alleviation of either or both concurrent disorders.