Decreased reward during acute alcohol withdrawal in rats selectively bred for low alcohol drinking

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We have previously hypothesized that increased sensitivity to the dysphoric-like or aversive effects of alcohol withdrawal following an
initial exposure to alcohol might be associated with a genetic propensity to avoid alcohol. A decrease in brain reward function, as measured
by an elevation in intracranial self-stimulation (ICSS) reward threshold, is one of the few methods available to model dysphoric-like or
aversive effects of drug withdrawal in rats. We compared brain reward function during withdrawal following an initial exposure to alcohol
in alcohol-naı¨ve rats selectively bred for high (HAD1 line) versus low (LAD1 line) voluntary alcohol consumption. Male HAD1 (n55) and
LAD1 (n56) rats were implanted with unilateral electrodes in the medial forebrain bundle and trained to bar press for delivery of a 100 mA
current that varied in frequency from 45 to 200 Hz. Responding for ICSS was generally stable within subjects across multiple experimental
sessions on a given day and across several consecutive days prior to alcohol or water administration. ICSS responding was assessed in both
rat lines prior to and at 12, 14, 16, 18, 20, and 24 h following a single intragastric infusion of alcohol (4.0 g/kg body weight) or water. Rats
of the LAD1 line, but not those of the HAD1 line, exhibited a decrease in brain reward function as evidenced by a decrease in bar-press
responding for ICSS and an increase in ICSS stimulation threshold during alcohol withdrawal. The results suggest that rats selectively bred
for low alcohol drinking may experience dysphoric-like effects during withdrawal from an initial exposure to alcohol, while rats selectively
bred for high alcohol drinking may not. 2006 Elsevier Inc. All rights reserved.

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Decreased reward during acute alcohol withdrawal in rats
selectively bred for low alcohol drinking
Julia A. Chestera,*, Edward J. Rauscha, Harry L. Juneb, Janice C. Froehlicha
aDepartment of Medicine, Indiana University School of Medicine, IB 424B, 975 W. Walnut Street, Indianapolis, IN 46202, USA
bDepartment of Psychology, Indiana University-Purdue University, Indianapolis, IN 46202, USA
Received 4 October 2005; received in revised form 16 June 2006; accepted 16 June 2006
Abstract
We have previously hypothesized that increased sensitivity to the dysphoric-like or aversive effects of alcohol withdrawal following an
initial exposure to alcohol might be associated with a genetic propensity to avoid alcohol. A decrease in brain reward function, as measured
by an elevation in intracranial self-stimulation (ICSS) reward threshold, is one of the few methods available to model dysphoric-like or
aversive effects of drug withdrawal in rats. We compared brain reward function during withdrawal following an initial exposure to alcohol
in alcohol-naı¨ve rats selectively bred for high (HAD1 line) versus low (LAD1 line) voluntary alcohol consumption. Male HAD1 (n55) and
LAD1 (n56) rats were implanted with unilateral electrodes in the medial forebrain bundle and trained to bar press for delivery of a 100 mA
current that varied in frequency from 45 to 200 Hz. Responding for ICSS was generally stable within subjects across multiple experimental
sessions on a given day and across several consecutive days prior to alcohol or water administration. ICSS responding was assessed in both
rat lines prior to and at 12, 14, 16, 18, 20, and 24 h following a single intragastric infusion of alcohol (4.0 g/kg body weight) or water. Rats
of the LAD1 line, but not those of the HAD1 line, exhibited a decrease in brain reward function as evidenced by a decrease in bar-press
responding for ICSS and an increase in ICSS stimulation threshold during alcohol withdrawal. The results suggest that rats selectively bred
for low alcohol drinking may experience dysphoric-like effects during withdrawal from an initial exposure to alcohol, while rats selectively
bred for high alcohol drinking may not. 2006 Elsevier Inc. All rights reserved.
Keywords: Intracranial self-stimulation (ICSS); Alcohol withdrawal; Aversion; Dysphoria; Selectively bred rat lines
1. Introduction
Alcohol withdrawal occurs in response to a reduction or
termination of alcohol exposure in both rats and humans
(American Psychiatric Association, 2000; Becker, 2000;
Edwards et al., 1981). Many of the signs of alcohol withdrawal
found in rats such as CNS hyperexcitability, body
temperature disruption, and anxiety (Baldwin et al., 1991;
Becker, 2000; Gallaher & Egner, 1987; Gatch & Lal,
1999; Holloway et al., 1993; Majchrowicz, 1975; Rassnick
et al., 1993; Spanagel et al., 1996) resemble those observed
in humans (Becker, 2000; Kalant, 1977). In both rodents
and humans, the magnitude of alcohol withdrawal is influenced
by genetics (McCaul et al., 1991; Newlin & Pretorius,
1990; Schmidt & Sander, 2000). Investigations of the
genetic relationship between alcohol withdrawal magnitude
and alcohol drinking in humans have reported mixed
results. On the one hand, individuals who are at low risk
for developing alcoholism because they carry a gene mutation
(ALDH2) show greater signs of alcohol withdrawal
than do individuals without this gene mutation (Wall
et al., 2000). On the other hand, individuals with an increased
genetic risk for alcoholism (sons of alcoholics)
show stronger signs of alcohol withdrawal than do individuals
without a genetic risk for alcoholism (sons of nonalcoholics)
(McCaul et al., 1991; Newlin & Pretorius, 1990;
Span & Earleywine, 1999). This discrepancy may be due
to differences in alcohol-drinking history in these studies,
which is known to influence the severity of alcohol withdrawal.
The amount, duration, and pattern of alcohol exposure
prior to alcohol withdrawal, as well as the extent of
prior alcohol withdrawal experience, can influence the severity
of alcohol withdrawal and the probability of subsequent
drinking in both rodents and humans (Becker &
Hale, 1993; Becker, 1994, 2000; Chapman, 1970; Hunter
et al., 1975; Kauhanen et al., 1997; Pawan, 1973; Swift
& Davidson, 1998). Rats selectively bred for high voluntary
alcohol drinking (high alcohol drinking [HAD] rat lines)
may be viewed as analogous to individuals at genetic risk
* Corresponding author. Purdue University, Psychological Sciences,
703 Third Street, West Lafayette, IN 47907-2081, USA. Tel.: þ1-765-
494-6863; fax: þ1-765-496-1264.
E-mail address: jchester@psych.purdue.edu (J.A. Chester).
0741-8329/06/$ e see front matter 2006 Elsevier Inc. All rights reserved.
doi: 10.1016/j.alcohol.2006.06.009
Alcohol 38 (2006) 165e172

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