Modeling the Diagnostic Criteria for Alcohol Dependence with Genetic Animal Models

Abstract

A diagnosis of alcohol dependence (AD) using the DSM-IV-R is categorical, based on an individual’s manifestation of three or more symptoms from a list of seven. AD risk can be traced to both genetic and environmental sources. Most genetic studies of AD risk implicitly assume that an AD diagnosis represents a single underlying genetic factor. We recently found that the criteria for an AD diagnosis represent three somewhat distinct genetic paths to individual risk. Specifically, heavy use and tolerance versus withdrawal and continued use despite problems reflected separate genetic factors. However, some data suggest that genetic risk for AD is adequately described with a single underlying genetic risk factor. Rodent animal models for alcohol-related phenotypes typically target discrete aspects of the complex human AD diagnosis. Here, we review the literature derived from genetic animal models in an attempt to determine whether they support a single-factor or multiple-factor genetic structure. We conclude that there is modest support in the animal literature that alcohol tolerance and withdrawal reflect distinct genetic risk factors, in agreement with our human data. We suggest areas where more research could clarify this attempt to align the rodent and human data.

Appendix

Sidebar. Mouse measures of tolerance and withdrawal severity in Tables 1 and 2

Trait	Description	Tabled variables	Reference
Hypothermic tolerance (standard inbred strains)	Mice were injected daily for 8 days with 3.0 g/kg EtOH. Initial hypothermic sensitivity was indexed as difference scores, each representing the reduction (on day 1) from baseline at 30 or 60 min after injection. Tolerance on days 3, 5, and 8 was indexed as the difference in post-injection change score from day 1 sensitivity score	Table 1, traits 1 and 2 tolerance on day 3 (e.g., HT chronic 30–3 and HT chronic 60–3) Table 1, traits 3 and 4, tolerance on day 5 Table 1, traits 5 and 6, tolerance on day 8	Crabbe et al. (1982)
Acute functional tolerance Loss of righting reflex (standard inbred strains)	Mice were injected with 3.0 g/kg EtOH. Blood samples were taken when they lost the righting reflex (i.e., were unable to turn over from a supine position) and when they regained it. The difference in blood EtOH concentrations (recovery minus initial loss) indexed AFT	Table 1, trait 7 AFT LORR	Ponomarev and Crabbe (2004)
Acute withdrawal (standard inbred strains)	Mice were injected with 4.0 g/kg EtOH and the handling-induced convulsion (HIC) was scored before, and hourly after for 12 h. Withdrawal severity was indexed as the area under the HIC curve corrected for baseline HIC	Table 1, trait 8 Acute WDR	Metten and Crabbe (1994)
Chronic withdrawal—continuous (standard inbred strains)	Mice were continuously exposed to EtOH vapor for 72 h at an average blood EtOH concentration of 1.6 mg/ml. Withdrawal HIC severity was assessed hourly for 10 h and again at 24 and 25 h. The average area under the 25 h HIC withdrawal curve for each strain was corrected by subtracting the area for HIC scores from a group exposed to air	Table 1, trait 9 Chronic Cont. WDR	Metten and Crabbe (2005)
Chronic withdrawal—intermittent (Standard inbred strains)	Mice were exposed to EtOH vapor for 16 h/day for 3 days at an average blood EtOH concentration of 1.7 mg/ml. Withdrawal HIC severity was assessed hourly for 10 h and again at 24 and 25 h. The average area under the 25 h HIC withdrawal curve for each strain was corrected by subtracting the area for HIC scores from a group exposed to air	Table 1, trait 10, Chronic Interm. WDR	Metten et al. (2010)
Hypothermic tolerance (BXD RI recombinant inbred strains)	Mice were injected daily for 3 days with 2.0, 3.0 or 4.0 g/kg EtOH. Initial hypothermic sensitivity was indexed as the average difference from baseline at 30 and 60 min after injection on day 1. Tolerance on days 3, 5, and 8 was indexed as the difference in post-injection change score from day 1 sensitivity scores	Table 2, traits 1–3 HT chronic 2 g/kg, HT chronic 3 g/kg, and HT chronic 4 g/kg	Crabbe et al. (1994, 1996)
Grid test tolerance (BXD RI recombinant inbred strains)	Mice were injected with saline for two days, and EtOH 2.0 g/kg on days 3,5,7,9, and 11. The grid test was used to assess foot fall errors through a wire mesh floor on each EtOH day, corrected for locomotion. Tolerance was indexed as the difference between ataxia ratios (foot falls/activity) on days 11 and 3	Table 2, trait 4 Grid test	Phillips et al. (1996)
Acute functional tolerance Dowel test (BXD RI recombinant inbred strains)	Mice were injected with 1.75 g/kg EtOH and placed on a stationary, 1.27 cm dowel, from which they soon fell. A blood sample was collected when they recovered ability to stay on the dowel (BEC1), and they were given a second, 2.0 g/kg injection. Another blood sample (BEC2) was taken when they again regained ability. AFT was indexed as BEC2 minus BEC1	Table 2, trait 5 AFT Dowel (Kirstein)	Kirstein et al. (2002)
Acute functional tolerance Dowel test (BXD RI recombinant inbred strains)	Mice were given an injection of 2.0 g/kg EtOH. Brain EtOH levels were taken within 10 s of fall from a rotating, 5 cm dowel to assess initial sensitivity. Separate groups of mice were given the initial 2.0 g/kg injection, and when they recovered ability to stay on the dowel, a blood sample was taken. Mice were then given a “booster” dose of 1.0 g/kg and a second recovery was assessed. Four to five booster doses were given until each RI strain of mice was recovering function at a stable plateau of blood EtOH concentrations. The difference between the final and the initial brain EtOH concentration was taken as the index of tolerance	Table 2, trait 6 AFT Dowel (Gallaher)	Gallaher et al. (1996)
Acute withdrawal (BXD RI recombinant inbred strains)	Same as for standard inbreds	Table 2, trait 7 Acute WDR	P. Metten and J.K. Belknap, unpublished data, with permission
Chronic withdrawal—continuous (BXD RI recombinant inbred strains)	Same as for standard inbreds. Average blood EtOH concentration was 1.5 mg/ml	Table 2, trait 8 Chronic cont. WDR	Crabbe (1998)