Blackwell Publishing LtdOxford, UKADBAddiction Biology1355-6215 2006 The Author(s).

Journal compilation 2006 Society for the Study of Addiction

2006
00
Original Article
Excessive ethanol drinking in P rats
Richard L. Bell et al.

REVIEW doi:10.1111/j.1369-1600.2006.00029.x

The alcohol-preferring P rat and animal models of

excessive alcohol drinking
Richard L. Bell1, Zachary A. Rodd1, Lawrence Lumeng2,3, James M. Murphy1 &
William J. McBride1,3
Departments of Psychiatry1, Medicine2 and Biochemistry3, Indiana University School of Medicine, USA

ABSTRACT

The alcohol-preferring, P, rat was developed by selective breeding to study ethanol drinking behavior and its conse-
quences. Characterization of this line indicates the P rat meets all of the criteria put forth for a valid animal model of
alcoholism, and displays, relative to their alcohol-non-preferring, NP, counterparts, a number of phenotypic traits asso-
ciated with alcohol abuse and alcoholism. Behaviorally, compared with NP rats, P rats are less sensitive to the sedative
and aversive effects of ethanol and more sensitive to the stimulatory effects of ethanol. Neurochemically, research with
the P line indicates the endogenous dopaminergic, serotonergic, GABAergic, opiodergic, and peptidergic systems may
be involved in a predisposition for alcohol abuse and alcoholism. Paralleling the clinical literature, genetically selected
P rats display levels of ethanol intake during adolescence comparable to that seen during adulthood. Binge drinking has
been associated with an increased risk for health and other problems associated with ethanol abuse. A model of binge-
like drinking during the dark cycle indicates that P rats will consume 6 g/kg/day of ethanol in as little as three 1-hour
access periods/day, which approximates the 24-hour intake of P rats with free-choice access to a single concentration
of ethanol. The alcohol deprivation effect (ADE) is a transient increase in ethanol intake above baseline values upon re-
exposure to ethanol access after an extended period of deprivation. The ADE has been proposed to be an animal model
of relapse behavior, with the adult P rat displaying a robust ADE after prolonged abstinence. Overall, these findings indi-
cate that the P rat can be effectively used in models assessing alcohol-preference, a genetic predisposition for alcohol
abuse and/or alcoholism, and excessive drinking using protocols of binge-like or relapse-like drinking.

Keywords Genetic, selection, ethanol, reward, reinforcement, conditioning.

Correspondence to: Richard L. Bell, Indiana University School of Medicine, Institute of Psychiatric Research, 791 Union Drive, Indianapolis, IN 46202,
USA. E-mail: ribell@iupui.edu

REVIEW

INTRODUCTION These concerns stemmed from the fact that, in general,

Animal models have been successfully used in developing
treatments for a number of medical and psychiatric dis-
orders (e.g. McKinney 2001; Griffin 2002). An animal
model has the advantage of allowing the experimenter to
control characteristics of the animals genetic back-
ground, environment and prior drug exposure. In addi-
tion, an animal model allows for the examination of
neurobehavioral, neurochemical and neurophysiological
correlates with the behavioral, physiological or neurolog-
ical state that is modeled. These correlates in turn
facilitate the development of pharmacological and/or
behavioral treatments for the disorder in question. There
have been reservations as to whether a valid animal
model of alcoholism could be developed (Cicero 1979).
experimental manipulations [e.g. fluid deprivation
(Sandi, Borrell & Guaza 1990), schedule-induced poly-
dipsia (Meisch 1976), scheduled availability (Holloway,
Bird & Devenport 1984), sucrose-fading (Samson 1986)
and forced induction of dependence (Deutsch & Eisner
1977; also cf. Roberts et al. 2000)] are required to induce
appreciable levels of ethanol self-administration in com-
mon stock rats. Nevertheless, certain criteria for an ani-
mal model of alcoholism have been put forth (Lester &
Freed 1973; Cicero 1979). Briefly, these criteria are as fol-
lows: (1) the animal should orally self-administer etha-
nol; (2) the amount of ethanol consumed should result in
pharmacologically relevant blood ethanol levels; (3) eth-
anol should be consumed for its post-ingestive pharma-
cological effects, and not strictly for its caloric value or

2006 The Authors. Journal compilation 2006 Society for the Study of Addiction Addiction Biology, 11, 270288

taste; (4) ethanol should be positively reinforcing, in
other words, the animals must be willing to work for eth-
anol; (5) chronic ethanol consumption should lead to the
expression of metabolic and functional tolerance; and (6)
chronic consumption of ethanol leads to dependence, as
indicated by withdrawal symptoms after access to etha-
nol is terminated. More recently, a seventh criterion has
been proposed (cf. McBride & Li 1998). These authors
suggested that because alcoholics generally go through
episodes of abstinence and relapse (Burish et al. 1981;
Hilbrom 1990; McMillen 1997), an animal model of
alcoholism should also display characteristics associated
with relapse. One characteristic that should be displayed
is a loss of control when access to ethanol is reinstated fol-
lowing an extended period of ethanol abstinence. The
alcohol deprivation effect (ADE) is a transient increase in
ethanol consumption and/or preference for ethanol over
basal levels (average intake just prior to the deprivation
interval) displayed by animals when given free-choice
access to ethanol after a period of ethanol deprivation
(Sinclair & Senter 1967), and has been proposed to model
relapse-like behavior (e.g. Rodd et al. 2004b).
The alcohol-preferring P rat
Through bidirectional selective breeding, lines of rats
that display high or low ethanol-drinking phenotypes
based solely on selection history can be developed. Bidi-
rectional selection, from a heterogeneous foundational
stock, is accomplished through systematic mating of
non-siblings from the same extreme of the normal distri-
bution over successive generations, which results in
divergent lines that exhibit the extremes of ethanol pref-
erence. A major advantage of selective breeding is that
the high ethanol-consuming animals display this behav-
ior without environmental manipulations to induce eth-
anol preference.
The alcohol-preferring P and alcohol-non-preferring
NP lines of rats were developed by mass selection from a
Wistar foundation stock (Lumeng, Hawkins & Li 1977).
Regarding criteria for an animal model of alcoholism, P
rats drink greater than 5 g of ethanol/kg body weight/
day; whereas NP rats will drink less than 1 g/kg/day
under these same conditions (Li et al. 1987b). Moreover,
P rats attain pharmacologically relevant blood alcohol
concentrations (BACs, 50200 mg%) under 24-hour
and limited access conditions (Murphy et al. 1986; Rodd-
Henricks et al. 2001; Bell et al. 2006). P rats appear to
self-administer ethanol for its post-ingestive effects, as
indicated by the findings that these rats will self-
administer ethanol both intragastrically (Waller et al.
1984; Murphy et al. 1988) and directly into the ventral
tegmental area (VTA: Gatto et al. 1994; Rodd et al.
2005a,b,c). P rats will perform an operant response for
access to ethanol, indicating P rats will work for access to
2006 The Authors. Journal compilation 2006 Society for the Study of Addiction
Excessive ethanol drinking in P rats 271
ethanol and ethanol functions as a reinforcer (Murphy
et al. 1989; Files et al. 1998; Samson et al. 1998; McKin-
zie et al. 2000; Melendez et al. 2002; Rodd-Henricks et al.
2002a,b; Rodd et al. 2003). Whereas ethanol-nave P
and NP rats display similar levels of ethanol clearance (Li
& Lumeng 1977; Lumeng et al. 1982), P rats, given
chronic free-choice (free-choice indicating that food and
water are concurrently available with ethanol; i.e. the
animals are not deprived in any way) access to ethanol,
drink sufficient amounts to develop metabolic tolerance
(15% increase in ethanol elimination rate: Lumeng & Li
1986) and tolerance to the motor impairing/ataxic
(Gatto et al. 1987) and aversive (Stewart et al. 1991)
effects of ethanol. Furthermore, P rats develop depen-
dence with 24-hour free-choice drinking, as indicated by
physical signs upon ethanol withdrawal (Waller et al.
1982; Kampov-Polevoy et al. 2000). Regarding relapse-
like behavior, P rats will display an ADE after extended
periods (28 weeks) of deprivation (Rodd-Henricks et al.
2000b, 2001). Overall, the data indicate that the P line
satisfies the criteria proposed by Cicero (1979) and Lester
& Freed (1973) for an animal model of alcoholism,
including the additional criterion for the display of
relapse-like behavior (McBride & Li 1998). Table 1 lists
the proposed criteria for an animal model of alcoholism
and how the P line of rat fulfills these criteria.
Behavioral phenotypes
Studies of human subjects with a family history of alco-
holism suggest that there is an association between a low
level of response (or sensitivity) to ethanol and risk for the
development of alcoholism (Schuckit 1986, 1994). For
example, after an ethanol challenge, young adult family
history positive (for alcoholism) males (Schuckit 1985;
Schuckit & Gold 1988) and females (Lex et al. 1988) dis-
play less body sway than family history negative controls.
With regard to sensitivity, compared with NP rats, P rats
are less sensitive to the ataxic (Bell et al. 2001), hypoth-
ermic (Stewart et al. 1992), and aversive, as measured by
conditioned taste aversion (Froehlich et al. 1988) and
conditioned place aversion (Stewart et al. 1996), effects of
ethanol. The development of tolerance to the sedative-
hypnotic and motor-impairing effects of ethanol may per-
mit the alcoholic to drink greater amounts of alcohol over
time (Kalant, LeBlanc & Gibbins 1971). Therefore, an
association between ethanol preference and the develop-
ment of ethanol tolerance has been proposed (Tabakoff &
Ritzman 1979; Erwin, McClearn &Kuse 1980; Spuhler &
Deitrich 1984; L & Kiianmaa 1988). Regarding toler-
ance, P rats develop tolerance quicker than NP rats to the
ataxic (Bell et al. 2001) and hypnotic (Kurtz et al. 1996)
effects of ethanol. Additionally, chronic drinking by P rats
results in metabolic tolerance (Lumeng & Li 1986), func-
tional tolerance to the ataxic effects of ethanol (Gatto
Addiction Biology, 11, 270288
272 Richard L. Bell et al.

Table 1 Comparisons of the self-administration behavior of selectively bred P rats and proposed criteria for an animal model of alco-
holism (Lester & Freed 1973; Cicero 1979; McBride & Li 1998).

Animal model criteria Characteristics of P rats

Must orally self-administer ethanol under
free-choice conditions.
Ethanol self-administration should lead to
pharmacologically relevant blood alcohol
concentrations (BACs).
Ethanol should be positively reinforcing,
such that the animal will work for ethanol
access.
Ethanol should be self-administered for its
post-ingestive, pharmacological effects,
and not solely for its taste or for calories.
Chronic ethanol consumption should lead
to metabolic and functional tolerance.
Chronic ethanol consumption and
termination of ethanol access should
lead to physical signs of withdrawal.
After chronic consumption and a
prolonged deprivation period, the animal
should display relapse-like behavior.
Adolescent (McKinzie et al. 1998; Bell et al. 2003, 2006), and adult (Murphy et al.
1986; Rodd-Henricks et al. 2000b, 2001; Bell et al. 2006) P rats orally self-administer
greater than 5 g/kg/day ethanol under free-choice conditions.
Oral self-administration of ethanol by P rats results in average BACs of 50200 mg%
(Murphy et al. 1986; Rodd-Henricks et al. 2001; Bell et al. 2006)
P rats will operantly respond for ethanol, even with high workload (fixed-ratio)
requirements (Murphy et al. 1989; Files et al. 1998; Samson et al. 1998, Ciccocioppo,
Angeletti & Weiss 2001; Rodd et al. 2003), up to 30 or more bar presses for a single
0.1 ml ethanol dipper presentation (Ciccocioppo et al. 2001; Rodd et al. 2003).
P rats will operantly respond to self-administer ethanol intragastrically (Waller et al.
1984; Murphy et al. 1988) or directly into the ventral tegmental area (VTA: Gatto et al.
1994; Rodd et al. 2005a,b,c).
P rats drink sufficient amounts of ethanol to develop metabolic tolerance (Lumeng & Li
1986) and tolerance to the motor impairing (Gatto et al. 1987) and aversive effects of
ethanol (Stewart et al. 1991).
P rats develop dependence with 24-hour free-choice drinking, as indicated by physical
signs upon ethanol withdrawal (Waller et al. 1982; Kampov-Polevoy et al. 2000).
P rats will display an alcohol deprivation effect (ADE) after chronic consumption of
ethanol and long periods (28 weeks) of deprivation (Rodd-Henricks et al. 2000b,
2001).

et al. 1987), and increases the threshold for the aversive
effects of ethanol (Stewart et al. 1991).
It has been hypothesized that the stimulatory or
behaviorally activating effects of ethanol and other drugs
may be a manifestation of the reinforcing effects of
abused drugs (Wise & Bozarth 1987). Regarding the
stimulatory effects of ethanol, adolescent (Rodd et al.
2004) and adult (Waller et al. 1986) P rats display
greater locomotor activation after low doses of ethanol,
compared with NP rats. Furthermore, ethanol self-
administration results in increased locomotor activity
(Bell et al. 2002; Melendez et al. 2002) and heart rate
(Bell et al. 2002), compared with P rats self-administer-
ing water or saccharin. Using electroencephalographic
and event-related potential (ERP)-associated procedures,
the P rat displays greater stimulation under basal condi-
tions or following an ethanol challenge than NP rats
(Morzorati et al. 1988; Ehlers et al. 1991; Slawecki et al.
1999).
In general, the P line of rat displays many behavioral
and physiological characteristics found in alcoholics and
children of alcoholics, compared with non-alcoholics and
children of non-alcoholics. For example, family history
positive, for alcoholism, individuals display (1) lower sen-
sitivity to ethanol-induced motor impairment (Schuckit
1985; Lex et al. 1988; Schuckit & Gold 1988), which has
also been shown in P, compared with NP, rats following
low-to-moderate dose (1.0 g/kg) ethanol (Bell et al.
2001); (2) high novelty-seeking behavior, defined as
behavioral activation in the presence of an unknown
stimulus (Cloninger 1996), which appears to be predic-
tive of current and future alcohol abuse in humans
(Andrucci et al. 1989), similarly, in response to a novel
olfactory stimulus, P rats display greater increases in
activity than NP rats (Nowak et al. 2000); (3) greater
increases in heart rate after ethanol consumption than
family history negative subjects, and that non-alcoholic
family history positive individuals, compared with family
history negative individuals, display greater increases in
heart rate on the ascending side of the blood alcohol
curve (Conrod, Pihl & Ditto 1995; Conrod et al. 1997;
Conrod, Pihl & Vassileva 1998), regarding basic research,
P rats display increased heart rate when consuming eth-
anol, and this increase is greater and longer than that
seen after consuming other palatable solutions (e.g. sac-
charin, Bell et al. 2002), although studies comparing this
with NP and/or control lines have yet to be carried out;
and (4) regarding ethanol reinforcement, contextual
cues associated with drug (self-) administration and
mental representation of these cues can elicit auto-
nomic activation (OBrien et al. 1992; Childress et al.
1993; Rajan et al. 1998), and alcoholics display greater

2006 The Authors. Journal compilation 2006 Society for the Study of Addiction Addiction Biology, 11, 270288

autonomic activation in the presence of these cues, com-
pared with controls (e.g. Drummond, Cooper & Glautier
1990), similarly, P rats display increased heart rate in an
environment associated with ethanol self-administra-
tion, in the absence of ethanol (Bell et al. 2002, 2004a),
and P rats with prior home-cage access to ethanol display
this effect to a greater extent than those without prior
home-cage access (Bell et al. unpublished observations).
Regarding alcoholic typologies, P rats display many of the
characteristics associated with Cloningers Type 2 alco-
holic subtype (Cloninger 1987). For example, P rats
display (1) a genetic predisposition for high ethanol
consumption (cf. McBride & Li 1998; Murphy et al. 2002;
Bell et al. 2005); (2) display adult levels of ethanol con-
sumption during adolescence (discussed below, McKinzie
et al. 1999; Bell et al. 2003, 2006); and (3) display the
impulsivity/sensation-seeking discussed above (Nowak
et al. 2000). However, P rats do not appear to be more
aggressive than their NP counterparts or Wistar controls
(Bell et al. unpublished observations), a characteristic
often associated with the Cloninger Type 2 alcoholic
subtype.
Table 2 Comparisons of the self-administration behavior of selectively bred P rats and diagnostic criteria for alcohol abuse or depen-
dence (American Psychiatric Association 1994).
DSM-IV
Tolerance is displayed by either
(a) increased amounts of ethanol needed to
achieve desired effect or
(b) diminished effect with continued level of us
Alcohol is consumed to either
(a) avoid expression of withdrawal symptoms or
(b) to relieve withdrawal symptoms
Alcohol is consumed either
(a) in greater quantities or
(b) over a longer period than desired
Inability to control alcohol use
Excessive amount of time is spent in
(a) obtaining,
(b) using or
(c) recovering from the effects of alcohol
Alcohol use leads to forsaking important
(a) social,
(b) occupational and/or
(c) recreational activities
Alcohol use is continued despite knowledge of
persisting problems associated with alcohol use
DSM-IV, Diagnostic and Statistical Manual of Mental Disorders Fourth Edition.
2006 The Authors. Journal compilation 2006 Society for the Study of Addiction
Excessive ethanol drinking in P rats 273
Moreover, the ethanol self-administration behavior of
the P rat reveals some important parallels between an
animal model of alcoholism and criteria for a diagnosis of
alcohol abuse or alcoholism (Table 2), as put forth by the
Diagnostic and Statistical Manual of Mental Disorders
(Fourth Edition, DSM-IV: American Psychiatric Associa-
tion 1994). However, it should be kept in mind that the
analogy is done with a very broad interpretation, and the
animal model cannot relate to the societal consequences
implied in the DSM-IV criteria. For example, under
relapse conditions, the P rat does exhibit loss of control
over drinking, as illustrated by alcohol intakes reaching
46 g/kg within the first 2 hours after ethanol was
returned, but this may not be the same as that implied in
the DSM-IV criterion of inability to control alcohol use.
In addition, the DSM-IV criterion of excessive amount of
time obtaining or using alcohol may not be the same as
P rats spending a lot of the time in an operant session bar-
pressing for ethanol. Still, it is important to try to draw
parallels between human and animal studies, even with
the foreknowledge that there are weaknesses in such
parallels.
Characteristics of P rats
Chronic oral self-administration of ethanol leads to metabolic tolerance
(Lumeng & Li 1986), tolerance to the aversive effects of alcohol (Gatto et al.
1987; Stewart et al. 1991) and greater amounts consumed (Stewart et al.
1991).
Oral self-administration of ethanol is increased during and/or after withdrawal
of ethanol access (Rodd-Henricks et al. 2000b, 2001).
Chronic ethanol drinking leads to increased amounts consumed over time
(Stewart et al. 1991; Bell et al. 2003, 2006).
Reinstatement of ethanol consumption and the expression of an alcohol
deprivation effect (Rodd-Henricks et al. 2000b, 2001).
Will operantly respond for ethanol, even with high workload (fixed-ratio)
requirements (Murphy et al. 1989; Files et al. 1998; Samson et al. 1998;
Ciccocioppo et al. 2001; Rodd et al. 2003), up to 30 or more bar presses for a
single 0.1 ml ethanol dipper presentation (Ciccocioppo et al. 2001; Rodd et al.
2003).
Under limited access (Murphy et al. 1986; Nowak et al. 2000) or relapse-like
(Bell et al. unpublished observations; Rodd et al. unpublished observations)
conditions, will self-administer ethanol until impaired/intoxicated. Also, will
maintain their ethanol preference and volume of intake when nutritive and
non-nutritive, highly palatable solutions are concurrently available (Li et al.
1987a; Lankford et al. 1991).
Not able to test
Addiction Biology, 11, 270288
274 Richard L. Bell et al.
Neurochemical phenotypes
Regarding neurochemical correlates, clinical and basic
research indicate that the central nervous systems sero-
tonergic (5-HT, cf. Lovinger 1999), dopaminergic (DA, cf.
Heinz 2002), GABAergic and glutamatergic (cf. Davis &
Wu 2001), cholinergic (Ach, cf. Soderpalm et al. 2000),
opiodergic (cf. Herz 1997), peptidergic [e.g. neuropeptide
Y (NPY), cf. Heilig & Thorsell 2002] and hypothalamic-
pituitary-adrenal (HPA, cf. Gianoulakis et al. 1995; Keith
et al. 1995; Rasmussen et al. 2002) systems are involved
in alcohol abuse and alcoholism. Ethanol-nave P rats
have lower levels of 5-HT and 5-HIAA in cortical and
limbic regions than NP rats (adult: Murphy et al. 1982,
1987; weanling: Strother et al. 2005). Additionally,
there are fewer 5-HT immunostained fibers in the ante-
rior frontal cortex, accumbens and part of the ventral
hippocampus of ethanol-nave P rats, compared with NP
rats (Zhou et al. 1991a,b), with there being fewer 5-HT
immunostained neurons in the dorsal and median raphe,
as well (Zhou et al. 1991c). Ethanol-nave P rats have
lower levels of DA and its metabolites (DOPAC and HVA)
in limbic regions, compared with NP rats (adult: Murphy
et al. 1982, 1987; weanling: Strother et al. 2005). Zhou
et al. (1995) found fewer DA neuronal projections from
the VTA to the accumbens in ethanol-nave P rats rela-
tive to NP rats. Moreover, oral self-administration of eth-
anol, contingent on operant responding, was found to
increase extracellular DA levels to a greater extent in the
accumbens of P compared with Wistar rats (Weiss et al.
1993), suggesting that the VTA-DA system of the P rat
may be more sensitive to the reinforcing actions of etha-
nol than that of the Wistar rat. Ethanol-nave P rats also
have reduced numbers of D2 receptors in the VTA and
accumbens compared with NP rats (adult: McBride et al.
1993; periadolescent: Strother et al. 2003). Regarding
GABA, higher densities of GABAergic terminals were
identified in the accumbens of ethanol-naive P rats, com-
pared with NP rats (Hwang et al. 1990). Pertaining to
peptides, McBride et al. (1998) reported higher densities
of mu-opioid receptors in central nervous system (CNS)
limbic areas of ethanol-nave P relative to NP rats,
including the accumbens shell and core. Lower levels of
NPY were found in the amygdala, hippocampus, and
frontal cortex of ethanol-nave P, compared with NP, rats
(Ehlers et al. 1998). Similarly, lower levels of corticotro-
pin-releasing factor (CRF) were found in the amygdala,
hypothalamus, prefrontal cortex, and cingulate cortex of
ethanol-nave P, compared with NP, rats (Ehlers et al.
1992). Overall, the neurochemical differences observed
between the P and NP rat indicate that multiple neu-
rotransmitter and neuromodulatory systems may con-
tribute to the disparate alcohol drinking behaviors of
these lines.
2006 The Authors. Journal compilation 2006 Society for the Study of Addiction
In many instances, the innate neurochemical differ-
ences seen between ethanol-nave P and NP rats parallel
findings from both the basic and clinical literature. For
example (1) lower levels of CNS serotonin are also present
in high alcohol-drinking (HAD: Gongwer et al. 1989) and
Sardinian alcohol-preferring (sP: Casu et al. 2004; De
Montis et al. 2004) rats compared with their low alcohol-
drinking counterparts (low alcohol-drinking, LAD, and
Sardinian alcohol-non-preferring, sNP, respectively); (2)
lower levels of DA metabolites or DA D2 receptors are seen
in HAD (Gongwer et al. 1989) and sP (Stefanini et al.
1992), compared with LAD and sNP rats, respectively;
(3) increased levels of GABAergic terminals in the accum-
bens are seen in HAD, compared with LAD rats (Hwang
et al. 1990); (4) increased mu-receptor levels are seen in
high alcohol-consuming Alko Alcohol (AA) rats com-
pared with their low alcohol-consuming Alko Non-alco-
hol (ANA) counterparts (Soini et al. 1998, 1999); and (5)
lower levels of NPY content or NPY receptors are seen in
AA (Caberlotto et al. 2001) and HAD (Hwang et al. 1999)
rats compared with ANA and LAD rats, respectively.
These results highlight promising common differences
associated with disparate ethanol drinking behaviors
that should be considered for future studies. Regarding
the effects of ethanol, Katner & Weiss (2001) carried out
an elegant study from which they reported a significant
positive association between increases in extracellular DA
in the accumbens after an ethanol challenge and a pro-
pensity for high alcohol consumption using multiple lines
of selectively bred high alcohol-consuming, AA and HAD,
and low alcohol-consuming, ANA and LAD, lines of rats.
Additionally, as noted above, these authors had reported
a similar association using P and Wistar rats previously
(Weiss et al. 1993). The clinical literature indicates that
specific genetic polymorphisms of (1) the serotonin trans-
porter (SERT: Kweon et al. 2005); (2) the DA D2 receptor
(Konishi et al. 2004; Conner et al. 2005; Johann et al.
2005) and dopamine transporter (DAT: Khnke et al.
2005); (3) the GABA-A-alpha 2 receptor subtype (Eden-
berg et al. 2004; Lappalainen et al. 2005); and (4) NPY
(Lappalainen et al. 2002; Mottagui-Tabar et al. 2005) are
associated with the development of alcoholism.
The P rat and animal models of excessive
ethanol consumption
As can be seen from the above, substantial progress has
been made in determining neurobehavioral, neurophys-
iological and neurochemical phenotypes associated with
a genetic propensity to abuse ethanol. To a great extent,
this progress has been made with animal models of eth-
anol preference (of which the alcohol-preferring, P, ver-
sus alcohol-non-preferring, NP, pair of rat lines is but one
of several selectively bred high versus low alcohol-
consuming pairs of rat lines). Nonetheless, use of the P rat
Addiction Biology, 11, 270288
 Excessive ethanol drinking in P rats 275

line has also proved advantageous in examining binge-
like and relapse-like drinking. Binge drinking during high
school and college is becoming more prevalent and is also
a strong predictor of future ethanol-related problems in
both men and women in North America (Presley, Meil-
man & Lyerla 1994; Wechsler et al. 2000; Wechsler &
Nelson 2001; Bloomfield et al. 2003) and Europe (Gill
2002; Bloomfield et al. 2003; Kuntsche, Rehm & Gmel
2004; Gmel et al. 2006). The deleterious effects of etha-
nol abuse on societal health are staggering (cf. Brienza &
Stein 2002; Room, Babor & Rehm 2005). Average vol-
ume of ethanol consumed is generally the major factor
contributing to the onset and development of these med-
ical conditions (cf. Rehm et al. 2003; Room et al. 2005).
However, pattern of drinking, specifically irregular heavy
usage (binge-like drinking), appears to play as large a
role, if not larger, in the onset and development of some
diseases (e.g. cardiovascular disease: Rehm et al. 2003;
Room et al. 2005).
The National Institute on Alcohol Abuse and Alcohol-
ism (NIAAA) National Advisory Council (2004) has
adopted the following definition of binge drinking: A
binge is a pattern of drinking that brings BAC to
80 mg% or above. For the typical adult, this pattern cor-
responds to consuming five or more drinks (male), or four
or more drinks (female), in about 2 hours. Binge drinking
is clearly dangerous for the drinker and for society. In the
above definition, a drink refers to half an ounce of alco-
hol (e.g. one 12-oz beer, one 5-oz glass of wine, or one
1.5-oz shot of distilled spirits). Binge drinking is distinct
from risky drinking (reaching a BAC between 50 and
80 mg%) and a bender (2 or more days of sustained
heavy drinking).
Given the criteria for a valid animal model of alcohol-
ism, discussed above, along with the definitions of binge,
and bender, drinking in clinical populations, we propose
that an animal model of excessive ethanol drinking
should exhibit certain criteria (Table 3). Excessive etha-
nol consumption should produce repeated, sustainable
BACs in the range of 100 mg% or higher. Excessive etha-
nol drinking should be demonstrated under free-choice
conditions in which water, or another palatable solution,
is available in addition to the ethanol. Ethanol should be
consumed for its post-ingestive CNS effects and not solely
due to taste factors or caloric value; in addition, excessive
ethanol consumption should not be a result of fluid dep-
rivation. An excessive ethanol drinking protocol should
produce signs of intoxication (e.g. motor impairment),
and should result in the development of tolerance to
ethanol-induced effects (e.g. motor impairment/sedative
effects), and signs of physical dependence. Some of these
criteria, e.g. sustainable BACs greater than 100 mg%,
have been proposed by others, as well (e.g. Rhodes et al.
2005).
Previous work from our laboratory indicated that P
rats consume most of their ethanol in bouts during the
dark cycle (Murphy et al. 1986). A bout is defined as a
cluster of drinking behavior that is sufficiently aggre-
gated such that the organism must stop ongoing behavior
in order to carry out this cluster of drinking behavior.

Table 3 Criteria for an animal model of excessive ethanol consumption.

Proposed criteria Characteristics of P rats

Excessive ethanol consumption should produce
repeated, sustainable blood alcohol
concentrations (BACs) of 100 mg% or greater.
Excessive ethanol consumption is displayed
under voluntary free-choice conditions.
Ethanol is consumed for its post-ingestive central P rats consume ethanol for its post-ingestive effects (Waller et al. 1984; Murphy
nervous system effects and not solely due to
taste, caloric value, or fluid deprivation.
Signs of intoxication (e.g. ataxia) are displayed
following an episode of excessive ethanol
consumption.
Tolerance to ethanol-induced effects develops
following chronic excessive ethanol drinking.
Signs of dependence are displayed after chronic
excessive ethanol consumption and withdrawal.
P rats achieve BACs of 100 mg% or greater under
1. Binge-like conditions: drinking-in-the-dark multiple scheduled access
(Fig. 2).
2. Relapse-like conditions: expression of an alcohol deprivation effect, with
home-cage (Rodd-Henricks et al. 2000b, 2001) or operant
self-administration (Rodd et al. 2003).
P rats display excessive ethanol consumption under binge-like (Fig. 2) and
relapse-like conditions (Fig. 4, Rodd-Henricks et al. 2000b, 2001), with food and
water available ad libitum.
et al. 1988); excessive ethanol consumption does not require addition of
sweeteners, or food or fluid deprivation (Rodd-Henricks et al. 2001; Figs 2 and 4).
Anecdotally, P rats display a loss of righting reflex after binge-like (Bell et al.
unpublished observations) and relapse-like (Rodd et al. unpublished
observations) ethanol consumption.
Has not been tested.
Has not been tested.

2006 The Authors. Journal compilation 2006 Society for the Study of Addiction Addiction Biology, 11, 270288
276 Richard L. Bell et al.
For example, a brief interruption of feeding behavior to
obtain fluid in order to soften the food, with an immediate
return to feeding behavior, would not be considered a
bout, at least not in the present context. However, a
period of fluid consumption upon waking, generally sub-
stantial across species, to replenish fluids lost during sleep
would be considered a bout of drinking behavior, within
this context. The circadian microstructure of ethanol self-
administration by P rats has not been evaluated. There-
fore, in a recent study, our laboratory examined free-
choice home-cage ethanol (15%) drinking behavior of
male and female, periadolescent and adult P rats. It was
found that, in general, male and female P rats will con-
sume ethanol in discrete bouts across the dark cycle dur-
ing which amounts of 1 g/kg/bout ethanol or greater are
self-administered (Bell et al. 2006). In Fig. 1, the individ-
ual licking patterns for eight adult female P rats on their
30th day of ethanol access are depicted. These individual
records indicate that (1) there is some heterogeneity in
ethanol licking behavior (e.g. the estimated licking
requirement to self-administer 1 g/kg of ethanol per bout,
see below, differs markedly between some animals)
among adult female P rats, despite their sharing a com-
mon genetically selected phenotype of ethanol preference
over water; (2) the animals consumed ethanol in discrete
bouts with the number of licks displayed often exceeding
the number required to self-administer 1 g/kg of ethanol
per bout (estimated number of licks to self-administer
1 g/kg/bout = total licks on the ethanol bottle per day
divided by the total g/kg ethanol self-administered per
day: horizontal bar in graphs); (3) these bouts often
occurred in time spans of 6 minutes or less, which sug-
gests appreciable (90 mg% or higher) blood ethanol con-
centrations are achieved repeatedly (cf. Murphy et al.
2002); and (4) total time per day spent consuming etha-
nol was 1 hour or less for most animals. Additionally, the
individual licking patterns for adult male P rats revealed
these same characteristics (Bell et al. 2006).
An animal model of binge-like drinking
Given the P rats propensity for bout-like drinking of eth-
anol during the dark cycle, we have examined their drink-
ing behavior when given multiple 1-hour access periods
across the dark cycle (Bell et al. 2004b), and this proce-
dure [drinking-in-the-dark multiple scheduled access
(DID-MSA)] has been used to assess the consequences of
binge-like drinking in these rats (e.g. proteomic changes
following binge-like access to ethanol: Kimpel et al.
2005). Toward this end, our laboratory has implemented
the use of concurrent access to multiple concentrations of
ethanol in studies examining excessive ethanol consump-
tion. This addition to our protocols resulted from findings
that the concurrent availability of multiple concentra-
tions of ethanol increases ethanol intake in adult outbred
2006 The Authors. Journal compilation 2006 Society for the Study of Addiction
rats (Wolfgramm & Heyne 1995; Holter et al. 1998) and
adult (Rodd-Henricks et al. 2001) and periadolescent
(Bell et al. 2003) selectively bred P rats. In one study of
binge-like drinking, adult male P rats were given concur-
rent, free-choice access to 15% and 30% ethanol. Ethanol
access was given 5 days per week, with 24-hour access
during the first 2 weeks and two 1-hour access sessions
for the next 4 weeks. Animals were housed on a reverse
light-dark cycle (lights off 09:00 hour), with the first 1-
hour access period starting at lights out (09:00 hour),
and the second 1-hour access period starting at
13:00 hour. On the first ethanol access day of the seventh
week, animals were given their usual 09:00 hour
through 10:00 hour access period, and sacrificed at
10:00 hour to evaluate trunk BACs. According to the
record of ethanol licking behavior, greater than 95% of
the ethanol was consumed in the first 12 minutes of this
1 hour access session (Fig. 2, lower panel). As seen in
Fig. 2 (upper panel), there was a strong correlation
between amount of ethanol consumed and BAC
achieved: r = 0.81, P < 0.001 (Bell et al. unpublished
findings).
In another study using the DID-MSA procedure, adult
male P rats were given concurrent access to 15% and
30% ethanol, with ad lib access to water and, except
where indicated, food. Rats were housed on a 12-hour
reverse dark-light cycle (lights off 09:00 hour). For the
binge-like group, ethanol was made available 5 days a
week, with three 1-hour access periods spaced 2 hours
apart, starting 1 hour into the dark cycle (10:00 hour).
On the first ethanol access day of the 9th week, continu-
ous access animals (24-hour/day) were sacrificed at
10:00 hour (after their first hour in the dark), and the
binge-like animals were sacrificed at 11:00 hour (after
their first hour of ethanol access), to evaluate trunk
BACs. Half of the continuous animals had their food
removed at dark onset (09:00 hour), and half of the DID-
MSA animals had their food removed at the beginning of
their 1-hour ethanol access period (10:00 hour). As seen
in Fig. 3 (upper panels), there was a strong correlation
between amount of ethanol consumed and BAC ac-
hieved: r = 0.82, P = 0.003; r = 0.92, P < 0.001, for the
continuous (A) and binge-like animals (B), respectively
(Bell et al. unpublished findings). Note that the 1 hour of
food restriction essentially doubled the BACs achieved
without significantly affecting overall ethanol intake (i.e.
the two continuous groups, essentially, drank the same
amount of ethanol, with a similar effect seen for the
binge-like animals). The reduced BACs seen in binge-like
rats in Fig. 3, compared with Fig. 2 (upper panel), may
have been due to lower food intake in binge-like rats of
Fig. 2 (these animals had the beginning of their first hour
of ethanol access coincide with lights off, whereas the
binge-like rats in Fig. 3, had the beginning of their first
Addiction Biology, 11, 270288
 Excessive ethanol drinking in P rats 277

Figure 1 For descriptive purposes, individual ethanol licking patterns for eight adult female P rats on the 30th day of ethanol access are pre-
sented. It is noteworthy that the ethanol licking behavior of female P rats is a heterogeneous phenomenon, with different rats displaying dif-
ferent patterns of drinking and/or different estimated number of licks [total licks per day/total ethanol (g/kg) consumed per day] to self-
administer 1 g/kg of ethanol per bout. By the 30th day of ethanol access, adult female P rats were self-administering an estimated 1 g/kg body
weight of ethanol in bouts taking less than 6 minutes to complete (each vertical bar represents a 6-minute bin), with the total time spent con-
suming ethanol per day being less than 1 hour for many animals. The horizontal lines indicate the estimated number of licks required to self-
administer 1 g/kg/bout of ethanol. The number in the upper right corner refers to the subject ID

2006 The Authors. Journal compilation 2006 Society for the Study of Addiction Addiction Biology, 11, 270288
278 Richard L. Bell et al.
Figure 2 Blood alcohol concentrations (BACs) achieved and
amount of ethanol consumed by adult male P rats during the first
hour of drinking on the seventh Monday of ethanol access, using a
drinking-in-the-dark multiple scheduled access (DID-MSA) proce-
dure. Animals had concurrent access to 15% and 30% ethanol 5 days
per week, with 24-hour access given the first 2 weeks, and two 1-
hour sessions per day, the first at the beginning of the dark cycle and
the second 3 hours later, for the remainder of the experiment. The
regression analysis of the amount of ethanol consumed and BAC lev-
els achieved revealed a significant correlation (r = 0.81, P < 0.001),
with the average amount consumed being 2.6 g/kg, and average BAC
achieved being 120 mg%, top panel. Evaluation of the ethanol licking
behavior revealed that practically all of the ethanol was consumed
within the first 12 minutes, bottom panel
hour of ethanol access start 1 hour after lights off).
Therefore, when using this model and the beginning of
the first hour of access coincides with lights off, P rats
achieve BACs exceeding criteria for binge-like drinking
(NIAAA National Advisory Council 2004).
The utility of the DID-MSA procedure stems from the
fact that P rats can self-administer approximately 2 g/kg/
1 hour session repeatedly. Depending upon the feeding
behavior of the rats (i.e. is the first hour of access initiated
at lights off, or is short-term food restriction imple-
mented), BACs exceeding 120 mg% are readily attained.
Note that these BACs may not reflect peak BACs, which
arguably may occur prior to the end of the 1 hour sched-
uled drinking session. When ethanol is made available for
2006 The Authors. Journal compilation 2006 Society for the Study of Addiction
three separate sessions (Fig. 3), then total ethanol intake
per day exceeds one of the original criteria for selective
breeding of the P line of rat (i.e. greater than 5 g/kg is self-
administered each day). These findings indicate that the
P rat can be effectively used in an animal model of binge-
like drinking. This model resembles human binge drink-
ing in that in any one ethanol access session, the P rat
attains BACs of at least 80 mg% within a 2-hour time
frame. However, this model does not resemble human
binge drinking, which does not usually occur in 5-day
patterns with three or four 1-hour sessions each day.
Nonetheless, excessive ethanol drinking is attained with
this limited access procedure, and this offers a model for
studying the neurobiological basis and consequences of
excessive ethanol consumption.
An animal model of relapse-like drinking
As indicated above, the NIAAA National Advisory Coun-
cil (2004) has adopted definitions of binge and bender
drinking. For binge drinking, an individual consumes
enough ethanol in a 2-hour period for their BAC to reach
and/or exceed 80 mg%. For bender drinking, the individ-
ual engages in sustained heavy drinking for at least
2 days. Although a formal BAC level was not indicated
when defining bender drinking, for the purpose of an
animal model, sustainable BACs in excess of 100 mg%
should be repeatedly achieved across days. For many indi-
viduals recovering from alcoholism, relapse is a monu-
mental problem (cf. Chiauzzi 1991; Weiss et al. 2001;
Barrick & Connors 2002; Jaffe 2002). In general, a
relapse is characterized by sustained heavy drinking
across days, which is the definition of a bender. The ADE
has been used to assess relapse-like behavior in P rats (e.g.
Rodd-Henricks et al. 2000b, 2001) and has been pro-
posed to be an animal model of alcohol relapse (e.g. Rodd
et al. 2004). The ADE is defined as a temporary increase
in the ratio of ethanol/total fluid intake and volume
of ethanol intake over baseline drinking conditions
(baseline = average ethanol consumption across the
3 days before the deprivation interval), when ethanol is
reinstated following a period of alcohol deprivation (Sin-
clair & Senter 1967). The ADE can be observed following
short (12-hour or less; Sinclair & Li 1989) or long (up to
75 days; Sinclair, Walker & Jordan 1973) deprivation
intervals. The ADE phenomenon has been reported in
humans (Mello & Mendelson 1972; Burish et al. 1981),
mice (Salimov et al. 1993), monkeys (Sinclair 1971; Kor-
net, Goosen & Van Ree 1990) and rats (Sinclair & Senter
1967; Heyser, Schulteis & Koob 1997). However, in stud-
ies with outbred animals (i.e. not selectively bred for
an ethanol preference), the ethanol intakes before and
after deprivation do not necessarily reflect high intakes,
such that blood ethanol levels achieved may not be
incapacitating.
Addiction Biology, 11, 270288
 Excessive ethanol drinking in P rats 279

Figure 3 Blood alcohol concentrations (BACs) achieved and amount of ethanol consumed by adult male P rats given either three 1-hour
free-choice access periods (the binge-like group), starting 1 hour into the dark cycle, and spaced 2 hours apart across the dark cycle or con-
tinuous ethanol access.The binge-like access animals had concurrent access to 15% and 30% ethanol 5 days per week, whereas the continuous
access animals had concurrent access to 15% and 30% ethanol 24 hours/day 7 days per week. The upper panels (a and b) depict the amount
of ethanol consumed and BACs achieved after the first hour in the dark for the continuous animals (a) and after the first hour of access for
the binge-like animals (b) on the ninth Monday of ethanol access. To assess the effects of 1-hour food restriction (open circles) half of each
group had their food removed at the beginning of the dark cycle (continuous) or beginning of their first hour of ethanol access (binge-like).
There were significant correlations between amount of ethanol consumed and BACs achieved for the continuous (r = 0.83, P = 0.003) and
binge-like (r = 0.92, P < 0.001) groups. One-hour food restriction resulted in significantly higher BACs achieved without affecting overall eth-
anol intake for both groups (continuous: 1.5 g/kg and 45 mg% versus 1.7 g/kg and 101 mg%; binge-like: 2.1 g/kg and 59 mg% versus 2.3 g/kg
and 129 mg%, for the ad lib and food restricted subgroups, respectively). The lower panel (c) indicates that the animals with three 1-hour eth-
anol access periods per day consumed approximately 6, or more, g/kg/day, whereas the animals with continuous access consumed approx-
imately 10, or more, g/kg/day. The lower panel (d) indicates that the amounts of ethanol consumed per hour by the binge-like access animals
during the third hour on Mondays (averaged across weeks) were higher than that seen for Fridays (averaged across weeks), but this did not
reach statistical significance (P > 0.05; i.e. there was no alcohol deprivation effect over the weekend)

In one study, with single deprivation periods of 2
8 weeks, and 24-hour free-choice access to 10% ethanol,
adult female P rats displayed increased ethanol intakes
from 5 g/kg/day (baseline), just prior to deprivation, to
around 9 g/kg/day on the first day of re-exposure to eth-
anol access (Rodd-Henricks et al. 2000b), which reflects
an 80% increase in ethanol drinking. Under these condi-
tions, ethanol intake returns toward baseline levels dur-
ing the second day. However, if multiple concentrations of
ethanol (10%, 20% and 30%) are concurrently available,
along with water, the intakes also increase by 80% on the
first day that ethanol access is restored, and this elevated
drinking is maintained on the second day of re-exposure
as well (Rodd-Henricks et al. 2001). To place this in the
context of basic research, with selectively bred high alco-
hol-consuming rats, it should be noted that in the HAD
replicate lines, the expression of an ADE is dependent
upon repeated deprivations, at least when a single con-
centration of ethanol is made available (Rodd-Henricks
et al. 2000a). Also, neither the AA (Hilakivi et al. 1984;
Sinclair & Tiihonen 1988; Sinclair & Li 1989) nor the sP
rat (Agabio et al. 2000) display an ADE across the first

2006 The Authors. Journal compilation 2006 Society for the Study of Addiction Addiction Biology, 11, 270288
280 Richard L. Bell et al.

24-hour period of ethanol re-exposure following an
extended (2-week) deprivation interval. Thus, the P
rat is unique among the selectively bred high alcohol-
consuming rat lines in the expression of an ADE following
a single extended deprivation period.
Research has indicated that the drinking pattern of
most alcoholics includes periodic intervals of voluntary
or imposed abstinence (cf. Finney & Moos 1991;
McMillen 1997). Because this is part of the criteria for
assessing relapse-like drinking in a valid animal model of
alcoholism (cf. McBride & Li 1998), the effects of repeated
deprivation cycles on relapse-like drinking in the P line of
rats has been examined. In an initial study with adult
female P rats, animals were housed on a reverse dark-
light cycle (09:00 hour lights off), and re-exposure was
initiated at dark onset (09:00 hour). This appears to limit
the effects of food in the stomach on ethanol absorption,
because rats are sleeping, for the most part, during the
light cycle. The rats had access to a single concentration
(10%) of ethanol for an initial 6 weeks, followed by three
cycles of 2 weeks of deprivation from and 2 weeks of re-
exposure to ethanol access. Multiple cycles of deprivation
resulted in an extended ADE (3 days of significantly ele-
vated ethanol intakes of 810 g/kg/day) compared with a
single day of elevated ethanol intake seen after a single
deprivation (Rodd-Henricks et al. 2000b). Moreover, the
group of P rats that were initially deprived for 8 weeks dis-
played a longer (up to 5 days) elevation in ethanol intake
after a second deprivation than the group initially
deprived for just 2 weeks (Rodd-Henricks et al. 2000b),
suggesting that neuronal alterations are occurring dur-
ing this deprivation period, which result in an extended
bender. In another study (Rodd-Henricks et al. 2001), in
which adult female P rats had concurrent access to mul-
tiple concentrations (10%, 20% and 30%) of ethanol and
water, the animals were taken through four cycles of
2 weeks of deprivation from and 2 weeks of re-exposure to
ethanol access following an initial 6 weeks of 24-hour,
free-choice drinking. Animals were housed on a reverse
dark-light cycle (09:00 hour lights off), and re-exposure
was initiated at dark onset (09:00 hour). Although
baseline alcohol intakes (around 6 g/kg/day) were not
significantly different from groups given only a single
concentration of ethanol, P rats given concurrent access
to multiple ethanol concentrations demonstrated a
marked increase (relative to values after the first
deprivation) in ethanol intake after a second deprivation
(1516 g/kg for the first 24 hours of re-exposure), with
elevated intakes extending into the fifth and sixth day by
the fourth re-exposure cycle (Rodd-Henricks et al. 2001).
Consequently, with concurrent access to multiple con-
centrations of ethanol, P rats consumed over 10 g/kg/day
of ethanol for 56 days meeting criteria for a bender
(NIAAA National Advisory Council 2004). Moreover,
during the first 2 hours of the fourth re-exposure (see
Fig. 4, upper panels), P rats consumed approximately 6 g/
kg ethanol and attained an average BAC of approximately
100 mg% by the end of this initial 2-hour re-exposure

Figure 4 Amounts of ethanol consumed and blood alcohol concentrations (BACs) achieved for adult female P rats following repeated dep-
rivations. The deprived animals had continuous, 24-hour, free-choice concurrent access to 10%, 20% and 30% ethanol for an initial 6 weeks,
which was followed by four (upper panels) or five (lower panels) cycles of 2 weeks of deprivation from and 2 weeks of re-exposure to eth-
anol. Regression analyses revealed significant correlations between amount of ethanol consumed and BACs achieved for both non-deprived
and deprived animals (rs > 0.75, Ps < 0.05). The graphs depict data for the first 2 hours of re-exposure to ethanol access (initiated at lights
off), such that the deprived animals readily displayed relapse-like behavior by consuming greater than 5 g/kg during the initial 2 hours of re-
exposure, with the average BAC exceeding 100 mg% upon the fourth re-exposure and approximating 150 mg% upon the fifth re-exposure

2006 The Authors. Journal compilation 2006 Society for the Study of Addiction Addiction Biology, 11, 270288

(Rodd-Henricks et al. 2001). When a fifth re-exposure
cycle was initiated, the BACs exceeded 100 mg%, with
many above 150 mg%, by the end of the initial 2 hours of
re-exposure (Fig. 4, lower panels). The robust increase in
drinking with repeated deprivations was a result of a shift
in preference from the lowest (10%) to the two higher
(20% and 30%) ethanol concentrations (Rodd-Henricks
et al. 2001). Overall, this pronounced increase in drink-
ing with repeated deprivations suggests that alterations
in the reinforcing and/or aversive effects of ethanol
occurred after a single extended deprivation period,
which, in turn, were enhanced after repeated
deprivations.
Using a repeated ADE protocol, with selectively bred P
or inbred P (derived from selectively bred P) rats, a num-
ber of important findings have been published. For exam-
ple, chronic ethanol drinking (over 6 months) resulted in
significantly increased self-administration of ethanol
directly into the posterior ventral tegmental area (pVTA),
compared with nave controls, and cycles of ethanol
access and deprivation (i.e. a repeated ADE protocol)
resulted in significantly greater self-administration of
ethanol into the pVTA, compared with the chronic drink-
ers (25 versus 30 versus 40 infusions of 75 mg% eth-
anol per session for the nave, chronic drinking and
repeatedly deprived rats, respectively: Rodd et al.
2005a,b). In another study, chronic ethanol drinking
(2 months) resulted in a significant increase in basal DA
neurotransmission in the accumbens, compared with
nave controls, which persisted for 2 weeks in the absence
of ethanol (Thielen et al. 2004). Additionally, these
authors reported that chronic drinking resulted in a sig-
nificant decrease in basal serotonin (5-HT) neurotrans-
mission in the accumbens of the same animals tested
above, compared with nave controls; whereas following
2 weeks of deprivation, this effect was reversed and
increased 5-HT release was observed (Thielen et al.
2004). In a third study, both inbred P rats that drank eth-
anol chronically (14 weeks) and those that experienced
repeated cycles of 2 weeks of deprivation from and re-
exposure to ethanol access (total of 10 weeks ethanol
access) displayed significantly greater D1 receptor bind-
ing densities in the anterior accumbens core, compared
with nave controls, with the repeatedly deprived group
displaying significant increases in D1 binding densities in
the anterior regions of the lateral and intercalated nuclei
of the amygdala as well (Sari, Bell & Zhou 2006). Addi-
tionally, these authors reported that both chronic drink-
ing and repeatedly deprived rats displayed significantly
greater D2 binding densities in the anterior accumbens
core and shell, compared with nave controls, with the
repeatedly deprived group also displaying significantly
increased D2 binding densities in the dorsal striatum, as
well (Sari et al. 2006).
2006 The Authors. Journal compilation 2006 Society for the Study of Addiction
Excessive ethanol drinking in P rats 281
Overall, these findings indicate that the P rat is highly
vulnerable to relapse-like drinking and is a good model for
studying mechanisms underlying this phenomenon. In
addition, the results reveal that two or more deprivations,
in conjunction with concurrent access to multiple con-
centrations of ethanol, can markedly exacerbate relapse-
like behavior, suggesting that additional neuronal alter-
ations are produced with repeated cycles of deprivation
and relapse. This repeated deprivation model has some
weaknesses with regard to the human condition, such
that the cycles of abstinence and relapse drinking are
regular, as opposed to being irregular in the human
alcoholic population. Nevertheless, the above results do
illustrate the compounding consequences of repeated epi-
sodes of alcohol withdrawals. Therefore, this model is
highly important for understanding the neurobiological
alterations that occur with repeated deprivations and
how these alterations contribute to relapse behavior.
Finally, the choice of gender to use in the binge and
relapse drinking experiments was based upon the avail-
ability of animals, i.e. if male P rats were available then
male rats were used, if female P rats were available, then
female rats were used. However, in chronic ethanol drink-
ing experiments in which stereotaxic surgeries are used,
it is necessary to use female P rats, because changes in
the head size and skull thickness are more dramatic in
male P rats, making stereotaxic placements much more
difficult. Results thus far indicate that there are no signif-
icant differences between male and female P rats in binge
and relapse drinking.
An adolescent animal model of ethanol abuse
Alcohol abuse among adolescents is a major health and
developmental problem. The prevalence of ethanol usage
is indicated by the findings that 7590% of high school
students report they have used ethanol (Zucker & Hart-
ford 1983; Fournet, Estes & Martin 1990; Windle 1990).
Excessive drinking, greater than five or more drinks per
occasion (a modified definition of binge drinking), has
been reported in approximately 30% of high school
seniors (Johnston, OMalley & Bachman 1991, 1993;
Rose et al. 2001), and there is evidence of ethanol use in
preadolescent children, as well (Quine & Stephenson
1990; Windle 1990). When assessing the effects of phar-
macological pretreatment during adolescence on adult
behaviors in male and female rats [as is done in our lab-
oratory (cf. McBride et al. 2005)], Spear (2000) has sug-
gested that the conservative estimate of an adolescent
window in rats [postnatal day (PND) 2842] could be
extended to PND 60. Our laboratory has adopted this
window of periadolescent exposure, and found that peri-
adolescent (PND 30 through 60) P rats will consume
amounts of ethanol that exceed one of the original crite-
ria [>5 g/kg/day (cf. McBride & Li 1998; Murphy et al.
Addiction Biology, 11, 270288
282 Richard L. Bell et al.
Figure 5 Amounts of ethanol consumed, g/kg/day, by periadoles-
cent [postnatal day (PND) 30 through 60] male and female P rats
given 24-hour, free-choice access to either a single concentration of
ethanol (15%, v/v) or concurrent access to multiple concentrations of
ethanol (10%, 20% and 30%, v/v). Overall (a) periadolescent P rats
readily self-administer ethanol during this stage of development (b)
animals with concurrent access to multiple concentrations of ethanol
consumed more ethanol than animal with access to a single concen-
tration of ethanol, and (c) the amounts of ethanol consumed exceed
one of the original criteria for selective breeding of P rats, such that
greater than 5 g/kg/day of ethanol is self-administered. *, indicates a
significant (P < 0.05) main effect of ethanol access condition (multiple
concentration versus single concentration) across weeks
2002; Bell et al. 2005)] for selective breeding of P rats
(McKinzie et al. 1999; Bell et al. 2003, 2006). Figure 5
shows the ethanol intakes of male and female P rats
beginning at 33 days of age (PND 33). Within the first
week, ethanol intakes have reached approximately 5 g/
kg/day for the group given access to a single concentra-
tion of ethanol (15%). Over the following 3 weeks ethanol
intake increased to approximately 8 g/kg/day. However, if
the periadolescent P rats were given concurrent access to
multiple concentrations of ethanol (10%, 20% and 30%),
ethanol intakes in the first week were approximately 8 g/
kg/day, with intakes increasing to around 10 g/kg/day by
PND 60. These results indicate that (1) P rats have early
onset high alcohol-consuming behavior; (2) this high
ethanol consumption can be exacerbated with access to
multiple concentrations of ethanol; and (3) there were
minimal gender differences in acquisition of ethanol
drinking during periadolescence.
Adolescent ethanol drinking may have enduring con-
sequences, as indicated by an association between early
onset of ethanol use and increased risk for later drug-
related problems (Chou & Pickering 1992; Anthony &
Petronis 1995), as well as general effects on brain devel-
opment and behavioral consequences (Spear 2000;
Chambers, Taylor & Potenza 2003). Research with the P
rat has revealed similar findings. For example, female P
rats given free-choice access to 15% ethanol during
2006 The Authors. Journal compilation 2006 Society for the Study of Addiction
periadolescence (PND 30 through PND 60) were exam-
ined for operant self-administration (in two-lever operant
chambers, with one lever for ethanol and one lever for
water) of ethanol during adulthood (>PND 75; Rodd-
Henricks et al. 2002a). Compared with ethanol-nave P
rats, animals that had access to ethanol during periado-
lescence displayed (1) quicker acquisition of operant self-
administration of ethanol; (2) retarded extinction (where
responding decreases to the point that pressing activity
on the ethanol bar does not differ from pressing activity
on the water bar) of this responding; and (3) a robust
operant ADE upon re-exposure to ethanol (Rodd-
Henricks et al. 2002a). In contrast, female P rats that
experienced pre-exposure to ethanol during adulthood
did not differ from ethanol-nave rats on these operant
parameters (Rodd-Henricks et al. 2002b). Additionally,
using microdialysis techniques, our laboratory has exam-
ined whether free-choice access to ethanol (15%) during
periadolescence (PND 3060) would alter the mesolim-
bic DA system during adulthood (>PND 75: Sahr et al.
2004). Compared with nave P rats, P rats with adoles-
cent access to ethanol displayed a greater extraction frac-
tion (a putative measure of DA reuptake/clearance from
the synaptic cleft), but not increased extracellular levels
of DA in the accumbens. Additionally, these same animals
displayed a more prolonged increase in accumbal extra-
cellular DA after a 2.5 g/kg (i.p.) challenge of ethanol
(Sahr et al. 2004). Therefore, ethanol drinking during
periadolescence can have long-lasting effects that may
increase the probability of initiating ethanol drinking
during adulthood and, by extension, interfere with the
ability to maintain abstinence during this period, as well.
Moreover, adolescent exposure to ethanol alters neuro-
circuitry (the accumbens as part of the mesolimbic DA
system) mediating ethanol reward, and this may be one
mechanism by which an individual develops a predispo-
sition to abuse ethanol.
CONCLUSION
The results reviewed above indicate that (1) the P rat
meets criteria proposed for a valid animal model of alco-
holism; (2) the self-administration behavior of the P rat
parallels many of the clinical criteria for a diagnosis of
alcohol abuse or alcoholism; (3) the P rat displays many
behavioral and neurochemical phenotypes seen in genet-
ically predisposed individuals and/or alcoholics; and (4)
the P rat displays excessive ethanol (binge-like or bender)
drinking with different environmental manipulations
including: concurrent access to multiple concentrations
of ethanol, multiple scheduled access intervals during the
dark period, and testing under relapse-like conditions.
Therefore, the P rat can be effectively used in models
assessing alcohol-preference, a genetic predisposition for
Addiction Biology, 11, 270288

alcohol abuse and/or alcoholism, the effects of ethanol
drinking during adolescence on adult behaviors, and
excessive drinking using protocols of binge-like or
relapse-like drinking. Pertaining to clinical typologies of
alcoholism, of which there are many (cf. Hesselbrock
1995), the P rat fits some of the criteria proposed by
Cloninger (1987) for the Type 2 alcoholic, in terms of
early onset of ethanol drinking, a genetic predisposition
to abuse ethanol, and the display of impulsive/sensation-
seeking behavior. However, the P rat does not necessarily
fit the behavioral phenotype of aggressive antisocial
behavior. In addition, both male and female P rats have
similar characteristics of ethanol drinking and its conse-
quences. These latter findings are not consistent with the
Type 2 classification, which, for the most part, is male-
specific (e.g. Babors classification subtype with charac-
teristics similar to Cloningers Type 2 was found among
both male and female alcoholics: Babor et al. 1992). It is
clear that much has been accomplished in determining
neurobiological factors associated with alcoholism, but,
at the same time, much has yet to be done. The P rat offers
many possibilities for advancing our understanding of
the neurobiological mechanisms underlying excessive
ethanol drinking, and ethanol relapse behavior. In addi-
tion, the P rat is one preclinical model of ethanol drinking
for screening potential therapeutic agents to treat alco-
holism and ethanol abuse.
Acknowledgements
The present work was supported in part by NIAAA
Grants AA 10256, AA 07611, AA 07462, AA 11261,
AA 13522 (an INIA project), and INGEN (supported in
part by the Lilly Foundation).
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