Richard L. Bell, PhD

I am Principal Investigator (PI) of the Rodents with Genetic Differences in Alcohol Preference U24.  The overall goal of this grant is to maintain an Alcohol Research Resource Center [in parallel with the Animal Production Core (APC) of the Indiana Alcohol Research Center (IARC)] so that these bidirectionally, selectively bred (alcohol-preferring, P, alcohol-nonpreferring, NP, high alcohol-drinking, HAD1 and HAD2, and low alcohol-drinking, LAD1 and LAD2 rats; as well as the high alcohol-preferring, HAP1, HAP2 and HAP3, and the low alcohol-preferring, LAP2 and LAP3, mice; along with the cHAP mice) rodent lines can be widely shared with off-campus alcoholism and drug addiction investigators at external research and academic institutions, ~60 different PI laboratories, around the world.  Regarding team science and multidisciplinary research, as Director of the U24 I have assisted numerous external investigators regarding experimental methodology, husbandry issues, and characteristics of the Indiana University selectively bred high (P, HAD1 and HAD2) and low (NP, LAD1 and LAD2) alcohol-consuming rat lines.  Moreover, I act as a consultant in describing basic behavioral and neurobiological phenotypic trait comparisons between the Indiana selectively bred rats and the other major international selectively bred HEC [Finnish, ALKO alcohol-accepting (AA); Italian, Sardinian alcohol-preferring (sP); Chilean, University of Chile B (UChB) and Polish, Warsaw high-preferring (WHP)] and LEC [Finnish, ALKO alcohol-non-accepting (ANA); Italian, Sardinian alcohol-non-preferring (sNP); Chilean, University of Chile A (UChA) and Polish, Warsaw non-preferring (WNP)] rat lines in the world, which were created in the 1960’s, 1970’2, 1950’s and 1990’s respectively.  The importance of these genetic animal models of high alcohol intake is that many of their characteristics parallel traits identified in human twin, family and adoptive studies, which indicate that genetic factors have a major role in the vulnerability to develop alcoholism.  Many investigators requesting these rats have never used selectively bred rats, and, in some cases, have never conducted alcohol-associated research.  Thus, my in-depth knowledge of these and other rodent animal models of alcoholism place me in an ideal position to advise numerous researchers around the world on the pros and cons of each rat line and differences between the respective rat lines.

Genotypically, the Quantitative Trait Loci (QTLs) associated with alcohol preference differ across the 3 Indiana selectively bred rat line-pairs.  This is true despite the fact that the same selection criteria (>5 g/kg/day ethanol intake, and >2:1 ratio of ethanol to water preference) as well as methodology were used to create them.  The QTLs for the P vs NP line-pair are located on chromosomes 3, 4 and 8; the QTLs for the HAD1 vs LAD1 line-pair are located on chromosomes 1, 5, 10, 12 and 16; and the QTLs for the HAD2 vs LAD2 line-pair are located on chromosomes 10 and 16 (for references and discussion see Bell et al., 2012).  The fact that the QTLs for alcohol preference and drinking patterns (Bell et al., 2008) are not the same across these 3 rat line-pairs suggests that these animal models may represent different alcoholic subtypes.  With that in mind, I collaborated with Drs. Bill McBride, Jeanette Mc Clintick, Larry Lumeng and Howard Edenberg locally and Drs. Giancarlo Colombo and Petri Hyytia, from Italy and Finland, respectively, to evaluate genomic differences between these major, international, selectively bred high ethanol-consuming (HEC) vs low ethanol-consuming (LEC) rat line-pairs.  Unexpectedly, our two studies found no single gene was significantly different, in the ventral tegmental area (VTA), nucleus accumbens shell (AcbSh) or medial prefrontal cortex (mPFC) between the HEC vs LEC rats in all 5 rat line-pairs (McBride et al., 2012, 2013).  Nevertheless, when the rat line-pair factor was collapsed (i.e., compared the HEC vs LEC rats across all 5 line-pairs) there were networks/gene clusters that differentiated the HEC from the LEC rats with gene expression level differences observed in both directions.  The clusters included “proliferation and migration of cells”, “transcription of DNA and cell proliferation”, “neurite outgrowth/neuronal migration”, “cell-to-cell signaling”, “cellular organization” and “cellular stress factors”.  Note, that all of these categories are involved in neuroplasticity; whether at the transcription, synaptic or neuronal level; a hallmark characteristic of chronic alcohol and drug abuse.  Thus, while all of these selectively bred rat line-pairs were developed using the same selection criteria and all were based, either totally or partially, on a Wistar background; there are subtle and not-so subtle differences suggesting they represent different animal models of diverse subtypes of alcoholics.

I am PI of a Medications Contract “Preclinical Medications Screening in P and HAD Rats” with NIAAA to test candidate drugs for the treatment of alcohol dependence.  With an increased emphasis on personalized medicine, previous and ongoing gene and gene system analyses are expected to inform the development of treatments/therapies.  Two recent publications (Bell et al., 2015; Franklin et al., 2015) from my laboratory have confirmed the utility of the selectively bred rat lines and their genomic information for medications development and screening.  Our genomic data indicate that gene expression levels of multiple phosphodiesterase 4 (Pde4) subtypes differ between HEC and LEC rats within subregions of the mesocorticolimbic reward circuit.  The Franklin et al (2015) study demonstrated that selective PDE4 inhibition significantly reduced ethanol intake by P and HAD1 rats; which replicated our previous work indicating that ibudilast, a nonselective PDE4 inhibitor, significantly reduced ethanol drinking by both P and HAD1 rats (Bell et al., 2015).  It is noteworthy that ibudilast has been fast-tracked, by the Food and Drug Administration (FDA), for the treatment of methamphetamine dependence.  Additionally, NIAAA and the National Institute on Drug Abuse (NIDA) are also assessing its efficacy for treating alcohol, and other drug, abuse/dependence in human laboratory studies.

In addition, I was a Co-I on Dr. Eric Engleman’s R01 “Long-Term Consequences of Voluntary Intake of Ethanol and Nicotine During Peri-Adolescence” contributing my expertise in modeling adolescent-type behaviors in rodents and selectively bred rat lines.  I have for a number of years researched ethanol-drinking during adolescence and young adulthood examining its neurobiological and neurobehavioral antecedents as well as consequences.  This is a burgeoning field of research and my colleagues (Drs. Bill McBride, Eric Engleman, Zac Rodd, Jamie Toalston, Kelle Franklin, Andy Chambers, Bill Truitt and Sheketha Hauser) and I have capitalized on the use of selectively bred HEC rats and their propensity to consume pharmacologically relevant levels of ethanol [blood ethanol levels (BELs) > 80 mg%] as well as nicotine [blood nicotine levels (BNLs) > 50 ng/ml].