Responsivity and Development of Tolerance to the Motor Impairing Effects of Moderate Doses of Ethanol in Alcohol-Preferring (P) and -Nonpreferring (NP) Rat Lines Richard L. Bell, Robert B. Stewart, James E. Woods II, Lawrence Lumeng, Ting-Kai Li, James M. Murphy, and William J. McBride Background: Research comparing the alcohol-preferring (P) and -nonpreferring (NP) rat lines has detected an apparent association between ethanol preference and lower responsivity to ethanol, as well as the capacity to develop and maintain tolerance to ethanol’s effects. However, past studies of tolerance to ethanol’s effects generally involved relatively high doses. The present study examined recovery from functional impairment induced by moderate doses of ethanol after a single dose (responsivity) and after multiple doses (development of tolerance) in the P and NP rat lines. Method: Adult female P and NP rats were trained, for 5 consecutive days, to stay on an oscillating bar for 120 sec. Rats were then assigned to one of three groups to receive 1.0, 1.25, or 1.5 g/kg ethanol for 5 consecutive test days. Rats were tested each day at 15-min intervals, following intraperitoneal injection, until recovery to the 120 sec criterion. Results: On the first test day, NP rats took longer to recover to criterion than the P rats following the 1.0 and 1.25 g/kg doses, whereas at the 1.5 g/kg dose no line difference was evident. Trunk blood alcohol concentrations (BACs), associated with time to recovery, indicated higher values for the P than NP rat on day 1 following injection of the two lower doses. Compared to day 1, NP rats demonstrated significantly shorter times to recovery beginning on day 2 following injections of the 1.0 and 1.25 g/kg doses. However, NP rats did not show significantly different recovery times on days 2–5 compared to day 1 following injection of the 1.5 g/kg dose. The shorter recovery times at the 1.0 and 1.25 g/kg doses were associated with BACs at recovery on day 3 being equal to or greater than values obtained on day 1. In contrast, compared to day 1, P rats did not show shorter recovery times until days 3 and 5 following the 1.0 and 1.25 g/kg doses, respectively. However, P rats did demonstrate shorter recovery times on day 2 and higher BACs on day 3 compared to day 1 following the 1.5 g/kg dose. Conclusion: With regard to motor impairment, lower responsivity to moderate doses of ethanol may be a factor associated with high alcohol-seeking behavior. The present results confirm past research support- ing an association between ethanol preference and low ethanol responsivity but at doses that are more reflective of those self-administered by P rats. Key Words: Alcohol, Responsivity, Tolerance, Oscillating Bar, Alcohol-Preferring Rats. C LINICAL RESEARCH INDICATES that a genetic predisposition plays a role in the development of alcohol abuse and alcoholism (Cloninger, 1987). Individu- als who are family history–positive (FHP) for alcoholism display lower motor impairment induced by ethanol com- pared with family history–negative (FHN) controls. For example, after an ethanol challenge, young adult FHP males (Schuckit, 1985; Schuckit and Gold, 1988) and fe- males (Lex et al., 1988) display less body sway than FHN controls. Also, young adult FHP males are less sensitive to the subjective and psychomotor signs of intoxication, com- pared with young adult FHN males (Schuckit, 1988). This has led Schuckit (1986, 1994) to propose an association between low level of response to ethanol and the develop- ment of alcoholism. Animal models have proven useful in the study of genetic factors, and selective breeding has been used to develop preference models such as the alcohol-preferring (P) and -nonpreferring (NP) rat lines (McBride and Li, 1998), with the P line satisfying criteria proposed as essential for an animal model of alcoholism (Lester and Freed, 1973). From the Departments of Psychiatry (RLB, JMM, WJM), Medicine (LL, T-KL), and Biochemistry, Institute of Psychiatric Research, Indiana Univer- sity School of Medicine and VA Medical Center (LL), and Department of Psychology (RBS, JEW, JMM), Purdue School of Science, Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana Received for publication September 14, 2000; February 7, 2001. Supported in part by NIAAA grants AA07462, AA07611, and AA10256. Reprint requests: Dr. William J. McBride, Indiana University School of Medicine, Institute of Psychiatric Research, 791 Union Drive, Indianapolis, IN 46202-4887; Fax: 317-274-1365; E-mail: wmcbride@iupui.edu Copyright © 2001 by the Research Society on Alcoholism. 0145-6008/01/2505-0644$03.00/0 ALCOHOLISM:CLINICAL AND EXPERIMENTAL RESEARCH Vol. 25, No. 5 May 2001 644 Alcohol Clin Exp Res, Vol 25, No 5, 2001: pp 644–650