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Lumeng, Lawrence, M.D.

Professor of Medicine & Biochemistry/Molecular Biology,
Indiana University School of Medicine,
Indianapolis, IN 46202

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Research Interests:
– alcoholic liver disease
– alcohol drinking behavior
– genetics of alcoholism

Recent evidence from more than 400 GWASs on human complex traits and disorders evinces that low frequency and rare alleles (some with large effects) are important in explaining the “missing heritability” in these clinical studies.  Selective breeding is a powerful genetic tool that directly creates animal models of human diseases and it will effectively “make” low frequency and rare variants more common and then “capture” them into the high and low lines. The high and low lines will exhibit phenotypes that greatly exceed the range found in the foundation stock. Since the 1970’s, scientists at Indiana University School of Medicine have created the selectively bred P/NP rat lines from a Wistar outbred stock (Wrm:WRC(WI)BR), the inbred P/inbred NP strains called iP10a and iNP1, and the HAD1-2/LAD1-2 replicate rat lines from the N/Nih HS stock (created from intercrossing 8 inbred rat strains).

Some of the outstanding features known about the Indiana P and HAD1-2 selected rats include the following: (1) The P, and to lesser extent, the HAD rats are the best characterized rodent models of human alcoholism. Except for the difficulty and impreciseness in defining human social behaviors to directly compare alcohol self-administration behavior of the P and HAD rats to human alcoholics, the P rats (to a lesser extent also the HAD 1-2 rats) fulfill at least four of the seven DSM-IV diagnostic criteria of alcohol dependence, i.e., the development of metabolic and behavioral tolerance to alcohol, the acquisition of physical dependence, inability to control alcohol use (the “alcohol deprivation effect” or ADE), and excess amount of time and effort spent to obtain alcohol. (2) Chronic intermittent alcohol vapor inhalation in stock rats and chronic free-choice alcohol drinking in the P rats are complementary models to study various aspects of alcohol dependence. (3) Studies in the P rats clearly demonstrated a major and primary role of the corticomesolimbic dopamine (DA) system in mediating ethanol’s CNS reward. The endogenous opioid system plays a secondary role. (4) Studies in the HAD1-2/LAD1-2 rat lines clearly indicate a role of impulsivity in initiating the early stages of alcohol misuse. (5) The P and the HAD rats are being used more and more for medication development to treat alcoholism. (6) Compared to Wistar stock and the NP rats, P rats self-administer more nicotine intravenously and orally.  Co-abuse of nicotine and alcohol occurs in >90% of alcoholics.  Accordingly, P rats are being used to develop medications to treat alcohol-nicotine co-abuse. (7) P and the HAD rats are the best characterized rodent models of binge-drinking and “relapse” and “out-of-control” drinking (ADE).  The rank order of ADE is P>HADs>sP>AA.  Although P and AA rats both prefer alcohol, P rats but not the AA rats develop a robust ADE with cycles of abstinence and reinstatement.

As summarized by a review by Murphy et al (2002), differences in serotonin, DA, glutamate, GABA, and opioids are responsible for the contrasting alcohol preference and alcohol seeking behavior seen in the P/NP and HAD1-2/LAD1-2 rat lines.  Central to the mesolimbic DA reward neurocircuit, the posterior ventral tegmental area (VTA) in the P rats is much more sensitive to self-infused ethanol than Wistar rats and this sensitivity to alcohol is dramatically increased with chronic alcohol drinking and alcohol deprivation.  Additionally, P rats in contrast to Wistar rats will self-infuse acetaldehyde into the posterior VTA and salsolinol into the posterior VTA and the nucleus accumbens.

Genomic analyses of the chromosome 4 QTL in the P rats by Carr/Liang et al have highlighted four top candidate genes for alcohol preference: NPY, Snca, GST8-8, and Crfr2.  Although human data are lacking to support the significance of GST8-8 and Crfr2 as susceptibility genes of human alcoholism, a number of translational studies have highlighted the relevance of NPY and Snca.  A polymorphism in NPY (Leu7Pro) was reported to be associated with alcohol dependence in human alcoholics.  In one COGA (Consortium on the Genetics of Alcoholism) study, NYP2R was found to be associated with alcohol dependence and withdrawal symptoms, comorbid alcohol/cocaine dependence, and cocaine dependence.  As well, NPY5R gene was associated with alcohol withdrawal characterized by seizures.  The cumulative evidence from NPY KO and transgenic mice, central infusion of NPY in P rats, and genomic analyses in congenic rats strongly implicates NPY as a foremost drug target for novel treatment of alcohol abuse and alcoholism.  Elevated Snca RNA and protein were found in alcoholics.  Additionally, COGA studies showed the Snca DNA sequence variants are linked to alcohol craving in alcoholics.

As part of the NIAAA-funded  Indiana Alcohol Research Center and an R24 National Research Resource Grant, we supply annually >3,500 P/NP and HAD1-2/LAD1-2 selected and inbred rats to both on-campus and off-campus alcohol researchers.


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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.