High Resolution Genomic Scans Reveal Genetic Architecture Controlling Alcohol Preference in Bidirectionally Selected Rat Model

Investigations on the influence of nature vs. nurture on Alcoholism (Alcohol Use Disorder) in human have yet to provide a clear view on potential genomic etiologies. To address this issue, we sequenced a replicated animal model system bidirectionally-selected for alcohol preference (AP). This model is uniquely suited to map genetic effects with high reproducibility, and resolution. The origin of the rat lines (an 8-way cross) resulted in small haplotype blocks (HB) with a corresponding high level of resolution. We sequenced DNAs from 40 samples (10 per line of each replicate) to determine allele frequencies and HB. We achieved ~46X coverage per line and replicate. Excessive differentiation in the genomic architecture between lines, across replicates, termed signatures of selection (SS), were classified according to gene and region. We identified SS in 930 genes associated with AP. The majority (50%) of the SS were confined to single gene regions, the greatest numbers of which were in promoters (284) and intronic regions (169) with the least in exon\u27s (4), suggesting that differences in AP were primarily due to alterations in regulatory regions. We confirmed previously identified genes and found many new genes associated with AP. Of those newly identified genes, several demonstrated neuronal function involved in synaptic memory and reward behavior, e.g. ion channels (Kcnf1, Kcnn3, Scn5a), excitatory receptors (Grin2a, Gria3, Grip1), neurotransmitters (Pomc), and synapses (Snap29). This study not only reveals the polygenic architecture of AP, but also emphasizes the importance of regulatory elements, consistent with other complex traits

Effects of SKF-83566 and haloperidol on performance on progressive ratio schedules maintained by sucrose and corn oil reinforcement: quantitative analysis using a new model derived from the Mathematical Principles of Reinforcement (MPR)

Rationale Mathematical models can assist the interpretation of the effects of interventions on schedule-controlled behaviour and help to differentiate between processes that may be confounded in traditional performance measures such as response rate and the breakpoint in progressive ratio (PR) schedules. Objective The effects of a D1-like dopamine receptor antagonist, 8-bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol hydrobromide (SKF-83566), and a D2-like receptor antagonist, haloperidol, on rats’ performance on PR schedules maintained by sucrose and corn oil reinforcers were assessed using a new model derived from Killeen’s (Behav Brain Sci 17:105–172, 1994) Mathematical Principles of Reinforcement. Method Separate groups of rats were trained under a PR schedule using sucrose or corn oil reinforcers. SKF-83566 (0.015 and 0.03 mg kg−1) and haloperidol (0.05 and 0.1 mg kg−1) were administered intraperitoneally (five administrations of each treatment). Running and overall response rates in successive ratios were analysed using the new model, and estimates of the model’s parameters were compared between treatments. Results Haloperidol reduced a (the parameter expressing incentive value) in the case of both reinforcers, but did not affect the parameters related to response time and post-reinforcement pausing. SKF-83566 reduced a and k (the parameter expressing sensitivity of post-reinforcement pausing to the prior inter-reinforcement interval) in the case of sucrose, but did not affect any of the parameters in the case of corn oil. Conclusions The results are consistent with the hypothesis that blockade of both D1-like and D2-like receptors reduces the incentive value of sucrose, whereas the incentive value of corn oil is more sensitive to blockade of D2-like than D1-like receptors