Same phenotype, different mechanisms: What five selectively bred rat lines reveal about the heterogeneity of human...

For seventy-five years, rats have been selectively bred for high voluntary alcohol consumption, yielding five major lines -UChB/UChA, P/NP, HAD/LAD, AA/ANA, and sP/sNP-msP- that share a behavioral phenotype but arose independently on three continents. This review argues that these lines are best understood as phenocopies: they reach high consumption via largely distinct biological routes rather than a single shared mechanism. Line by line, we synthesize the biochemical, genetic, and brain-circuitry explanations for the high-drinking phenotype, and compare them directly. The genetic architecture ranges from a single large-effect nonsense variant validated through a knockout in P rats, through a dispersed, predominantly regulatory polygenic architecture in HAD/LAD, to an enzyme-affinity locus with a direct human counterpart in UChB/UChA. Critically, a same-method comparison of all five lines reveals almost no molecular convergence at the level of individual genes, and in at least two neurotransmitter systems -opioid and CRF/stress- the direction of change associated with high consumption is directly opposite between lines. We read this as evidence that the heterogeneity of human alcohol use disorder is not merely an artifact of the difficulty of studying human populations, but a property of the phenotype itself. Because the line-to-subtype mapping is so far established for only two of the five lines, we frame the translational implication as a hypothesis rather than a prescription: that human AUD comprises mechanistically distinct subtypes, each corresponding to a different line's route to high consumption, best examined through prospective clinical stratification rather than by defaulting to any single model as definitive.