The major objective of this R24 Alcohol Research Resource nt is to supply to off-campus researchers at cost P/NP, HAD1-2/LAD1-2, and AA/ANA selectively bred rats, as well as HAP1-2-3/LAP2-3 and cHAP selected mice that show genetically high and/or low alcohol preference. (Specific Aims 2 and 3). The P/NP, HAD1-2/LAD1-2, HAP1-2-3/LAP2-3, and cHAP selected rodent lines were developed at Indiana University and this R24 is the sole funding source for maintaining the HAD1-2/LAD1-2 nucleus breeding colonies (Specific Aim 1). The HADl- 2/LAD1-2 lines from the N/Nih foundation stock are the only replicate rat lines selectively bred for divergent alcohol preference and they are phenotypically and genotypically different from the P/NP contrasting lines. In order to increase the value of this R24, a breeding colony ofAA/ANA rat lines will be transferred from Finland to Indiana as a new resource (Specific Aim 4). Neurochemically, AA rats are strikingly different from P rats, i.e., the mesolimbic dopamine pathway is not central either in the acquisition or maintenance of high alcohol preference in the AA rats;instead, innate neurocircuitries that involve endogeneous opioids and endocannabinoids appear to be the key. For the purpose of bringing further added value to this R24, Duke University will receive a subcontract to collaborate in creating a valid animal model of alcohol and nicotine co-abuse (Specific Aim 5). This approach is most expedient because Dr. Ting-Kai Li (the PI who created our P/NP, HAD1-2/LAD1-2, and HAP1-2/LAP1-2 selected rodent lines) is now a Professor of Psychiatry at Duke and Drs. Amir H. Rezvani and Edward D. Levin have active research programs at Duke that use iv nicotine self-administration routinely. This will be achieved by first comparing the five pairs of selectively bred rat lines with opposite alcohol preference (i.e., P/NP, HADl/LADl, HAD2/LAD2, AA/ANA, and sP/sNP) for their differences in willingness to self- administer nicotine by intraveneous route and to identify which high line has the highest proclivity to self- administer nicotine. This high line with both high alcohol drinking preference and high nicotine iv self- administration will then be used to investigate the effects of nondependent alcohol drinking and relapse-like alcohol drinking on nicotine self-administration.
Multiple alcohol-preferring rat lines from different genetic background are available, and together, they simulate behaviorally the distinct subtypes of alcoholics with high genetic load defined by a recent NESARC study. This R24 will supply to off-campus researchers the P/NP, HAD1-2/LAD1-2, and AA/ANA selectively bred rats as well as the HAP1-2-3/LAP2-3 and cHAP selected mice. Additionally, this R24 will create a new animal model of alcohol-nicotine co-abuse that will be extremely useful in basic preclinical research.
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