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The Journal of Neuroscience, 2001, 21:RC180:1-5
RAPID COMMUNICATION
Ethanol Consumption and Behavioral Impulsivity Are Increased in
Protein Kinase C Null Mutant Mice
Barbara J.
Bowers and
Jeanne M.
Wehner
Institute for Behavioral Genetics, University of Colorado, Boulder,
Colorado 80309
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ABSTRACT |
Etiological factors influencing the development of alcoholism are
complex and, at a minimum, include an interaction between polygenic
factors and personality and biological traits. Human and animal studies
suggest that some genes may regulate both the traits associated with
alcohol abuse, such as decreased sensitivity or anxiety, and
vulnerability to alcoholism. The identification of these genes could
elucidate neurochemical pathways that are important in the development
of alcohol abuse. Results from the present study indicate that the gene
encoding the neuronal-specific  subtype of protein kinase C (PKC)
influences both ethanol consumption and behavioral impulsivity, a
personality characteristic associated with Type II alcoholics, in a
pleiotropic manner. Mice lacking PKC consume more ethanol in a
two-bottle choice paradigm and also demonstrate increased behavioral
impulsivity in an appetitive-signaled nosepoke task when compared with
wild-type littermate control mice. Therefore, PKC may be an
important mechanism within the cell that mediates one or more
neurochemical pathways relevant to an increased predisposition to alcoholism.
Key words:
alcohol drinking; nicotine; impulsivity; PKC null
mutant mice; genetics; pleiotropy
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INTRODUCTION |
Several
studies of alcoholics and individuals at risk for alcoholism have
identified biological and personality trait markers that can be used to
predict a vulnerability to alcoholism (Cloninger, 1987 ; Finn et al.,
1992; Schuckit, 1998; Kushner et al., 2000). It is well accepted that
alcoholism is genetically influenced and that it is polygenically
regulated. Several biological and personality trait markers also appear
to be under genetic control (Marks, 1986; Schuckit, 1987; Goldman et
al., 1996; Young et al., 2000). Therefore, it may be that some of these
markers and the risk for alcoholism are genetically associated or are
the end result of pleiotropic influences of genes acting on both
behaviors. At-risk populations demonstrate low levels of responses
(i.e., initial sensitivity) to alcohol measured by cognitive and
psychomotor tasks, hormonal responses, and self-reports of intoxication
(for review, see Schuckit, 1987). Also, increased tolerance development in humans has been associated with a risk for alcoholism (Newlin and
Thomson, 1991).
In addition, subtypes of alcoholics have been categorized according to
personality characteristics. These are best exemplified by Cloninger's
(1987) Type I and Type II subgroups, although several other
investigators have reported similar findings (Finn et al., 1992;
Schuckit, 1998). Type I alcoholics are characterized by late onset of
alcohol abuse, increased anxiety, and low novelty-seeking behaviors. In
contrast, Type II alcoholics usually start drinking before age 25, demonstrate high novelty-seeking behaviors, are impulsive, and are
often socially aggressive. Recently, a genetic study of adolescent
twins indicated that behavioral disinhibition, a personality trait that
encompasses most of the Type II characteristics and drug
experimentation, is highly heritable (Young et al., 2000). A genetic
association between impulsivity and alcohol drinking has also been
shown in mice. Logue et al. (1998) reported a significant genetic
correlation between impulsivity and ethanol consumption in 13 inbred
strains of mice such that strains of mice that were more impulsive
drank more ethanol.
Recent results from this laboratory have indicated that the
neuronal-specific subtype of protein kinase C (PKC) is involved in several responses to ethanol and appears to regulate certain baseline behaviors. Using mice deficient in PKC, we have shown that
null mutant mice demonstrate decreased initial sensitivity to the
sedative-hypnotic and anxiolytic effects of ethanol when compared with
wild-type littermate controls (Harris et al., 1995; Bowers et al.,
1999, 2000b, 2001). PKC null mutants also display decreased
tolerance development to the sedative-hypnotic and hypothermic effects
of ethanol (Bowers et al., 1999, 2000b). Tests of anxiety-related behaviors in these mice indicated that baseline anxiety is reduced in
null mutant mice compared with wild-type control mice (Bowers et al.,
2000a).
On the basis of observations that compared with wild-type control mice
PKC mutant mice exhibit altered biological and behavioral phenotypes, some of which have been associated with a predisposition to
alcoholism in human populations, the present study investigated the
role of PKC in ethanol consumption. PKC null mutant and wild-type
littermates were tested for ethanol consumption and preference using a
24 hr access, two-bottle choice paradigm for ethanol drinking. Nicotine
preference was also measured in these genotypes to test for any
generalization of preference behavior to nicotine, a substance
frequently used in conjunction with alcohol drinking (Daeppen et al.,
2000). In addition, impulsive behavior was tested in these mice to
expand on behavioral phenotypes that may be genetically associated with
ethanol consumption.
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MATERIALS AND METHODS |
Animals
Male and female mice were 60-140 d of age at the time of
testing and were housed in like-sex groups of two to five. Mice were given food and water ad libitum and maintained on a 12 hr
light/dark cycle (lights on at 7:00 A.M.). PKC null mutant
mice were derived using gene-targeting and homologous recombination
techniques (Abeliovich et al., 1993) and are currently bred on a mixed
(F2) C57BL/6J × 129/SvEvTac genetic background at the Institute
for Behavioral Genetics (Boulder, CO) as described previously (Bowers
et al., 1999). Groups of null mutant and wild-type mice used in the
following experiments were derived from multiple F2 litters.
Ethanol preference
Data for the ethanol preference study were collected from two
experiments. Naïve male and female PKC null mutants
(n = 13) and wild-type littermate control mice
(n = 13) were housed individually and given food and
water ad libitum 24 hr before the start of ethanol testing.
Ethanol consumption and preference testing were performed using a 24 hr
access, two-bottle choice paradigm with mice receiving 4 d each of
five increasing concentrations of ethanol [3, 5, 7, 9, and 11%
(v/v)] and water. Food was available ad libitum. Ethanol
and water bottles were weighed and refilled each day. The weights were
used to calculate an ethanol preference ratio (volume consumed from the
ethanol bottles/total volume consumed from both water and ethanol
bottles). The amount of ethanol consumed was converted to grams per
kilogram per 24 hr. Body weights were measured every fourth day and did
not change as a function of ethanol concentration. In the first ethanol
experiment, mice were also tested for saccharin preference 2 d
after ethanol testing, using the same two-bottle choice paradigm, and
4 d each of three saccharin solutions (0.05, 0.1, and 0.2%).
Nicotine preference
Data for the nicotine preference study were collected from two
experiments. Naïve male and female null mutant
(n = 12) and wild-type littermate control
(n = 12) mice were housed individually for 4 d
before the start of testing and received food and water ad
libitum. The experimental paradigm was the same as that used for
ethanol preference: mice were given a choice between water and seven
increasing concentrations of nicotine (10, 20, 35, 50, 65, 80, and 100 µg/ml). Bottles were weighed daily, and the positions were rotated;
fresh nicotine solutions were placed in the cages every other day. Body
weights remained constant throughout the study. Nicotine preference
ratios and consumption (milligrams per kilogram per 24 hr) were
calculated the same as for ethanol preference and consumption.
Impulsivity testing
Data for the impulsivity testing were collected from three
experiments. Male and female PKC null mutant (n = 25) and wild-type littermate control (n = 25) mice were
used for testing.
Apparatus. Impulsivity testing was performed in four
identical Igloo ice chests (54 cm long × 30 cm high × 27 cm
deep) adapted for nosepoke training as described previously (Logue et
al., 1998). The reward was delivery of a 20 mg sucrose pellet (P. J. Noyes Company, Lancaster, NH) via a MED Associates pellet dispenser (St. Albans, VT). The auditory stimulus was a 3 sec, 80 dB, 6 clicks
per second train of clicks. The training chambers were interfaced to an IBM-compatible computer via a MED Associates interface
that was controlled with MED-PC software.
Procedure. Mice were trained in the nosepoke task as
described previously (Logue et al., 1998). Before training, all mice were deprived of food to 85% of their ad libitum body
weight (>8 d) and were maintained at this weight throughout training.
Training consisted of four phases. (1) Mice were reinforced for every
nosepoke on a preassigned left or right side (FR1). Phase 1 continued
until 25 reinforcements had been made in 30 min. (2) Mice were
reinforced for every third correct nosepoke (FR3) until 25 reinforcements had been made in 30 min. (3) In phase 3, the auditory
stimulus was introduced and consisted of 50 3 sec stimulus
presentations separated by an intertrial interval (ITI) of 30 sec.
Reinforcement occurred only on the first nosepoke on the reinforced
side during the auditory stimulus; however, all nosepokes during the
session were recorded. The nosepoke to the auditory stimulus was the
conditioned response (CR), and when 10 CRs were made in the 30 min
session, the mice moved to the final phase. (4) Each mouse received 10 daily, 30 min training sessions in phase 4. This phase was similar to
phase 3 except that the ITI was 20 sec followed by a 1-8 sec preauditory stimulus period. If the mouse nosepoked during this pseudorandomly varied preauditory stimulus period, the clock was reset;
this sequence continued until the mouse withheld responding for the
duration of this period. The next trial was then initiated immediately.
Withholding a response during this 1-8 sec period was important for
learning the auditory signal to the CR and for the mouse's ability to
control its nosepoke behavior. The dependent variables measured in this
task include the number of days to reach criterion for phases 1-3, the
percentage of conditioned responses (%CR) (the number of tone
trials on which a nosepoke was rewarded/total number of tone trials in
a session) in each session of phase 4, the efficiency ratio (the number
of reinforcements/total number of nosepokes in a session) in each of
the 10 sessions of phase 4, and the slopes of the efficiency ratio
curves. The efficiency ratios and slopes were used as the measures of impulsivity.
Data analysis
Data from the ethanol and nicotine experiments were analyzed
using repeated measures ANOVAs with drug concentration as the within
subjects factor and genotype and gender (ethanol experiment) as the
between subjects factors. Gender was not included in the nicotine
analyses because only 6 of 24 mice were female. Efficiency ratio and
percentage of conditioned response data from the signaled nosepoke task
were also analyzed using repeated measures ANOVAs with trial number as
the within subjects factor and genotype and gender as between subjects
factors. Student's t tests were used to compare genotypes
for days to criterion and to compare slopes of the efficiency ratio
curves between mutant and wild-type groups.
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RESULTS |
Ethanol consumption
PKC null mutant mice consumed significantly more ethanol (grams
per kilogram per 24 hr) than their wild-type littermate controls (Fig.
1C,D)
(F(1,22) = 9.63; p < 0.005). A statistical comparison of total fluid consumption (in
milliliters) indicated that mutant and wild-type mice did not differ in
the volume of liquid consumed (data not shown), indicating that the
increased ethanol consumption by the null mutants was not caused by an
overall increase in total amount of fluid consumed. There was also a
significant effect of gender, with female mice consuming more ethanol
than male mice (F(1,22) = 11.13;
p < 0.003) (Fig. 1C); however, the
genotype × gender interaction term was not significant,
indicating that both female and male mutant mice drank more than their
wild-type counterparts. Increased ethanol drinking by female mice has
been reported in selected lines of mice (Grahame et al., 1999),
recombinant inbreds (Rodriguez et al., 1994), and C57BL/6 mice
(Middaugh et al., 1999) and may involve sex-specific loci that
influence alcohol drinking (Peirce et al., 1998). Preference ratios
were also significantly greater in the null mutant mice (Fig.
1A,B)
(F(1,22) = 9.76; p < 0.005), with a significant gender effect
(F(1,22) = 6.89; p < 0.015). Female mutant mice exhibited the greatest preference for
ethanol over water at all concentrations (preference >50%), whereas
male wild-type littermate controls demonstrated no preference for
ethanol over water at any concentration (preference <36%) (Fig.
1A,B). Ethanol consumption levels
in the wild-type female mice are consistent with previous reports of
consumption in female C57BL/6 mice and are greater than that reported
for combined sexes of 129/SvEvTac mice. On the other hand, consumption
by male wild-type mice is less than that reported for C57BL/6 male mice
but is more consistent with intake levels in the 129/SvEvTac inbreds
(Belknap et al., 1993; Logue et al., 1998; Middaugh et al., 1999).
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Figure 1.
Ethanol preference and consumption were
significantly greater in PKC null mutant mice (n = 13) compared with wild-type control mice
(n = 13) (p < 0.005, p < 0.005; preference and consumption,
respectively). A and C illustrate that
preference and consumption were greater in female mice of
both genotypes (p < 0.015, p < 0.003; preference and consumption,
respectively) compared with male mice of both genotypes
(B, D).
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Saccharin preferences for the three concentrations ranged from 85 to
98% but did not differ between the genotypes, suggesting that
preference for sweet solutions was not a factor in the increased ethanol preference demonstrated by PKC null mutant mice (data not
shown). Results from the analyses of the nicotine data suggested that
PKC does not mediate nicotine consumption (milligrams per kilogram
per 24 hr) or nicotine preference (data not shown). Both genotypes
increased their consumption of nicotine as the concentration of
nicotine increased (F(6,31) = 36.45;
p < 0.0001), with no difference between PKC null
mutant and wild-type control mice. These results indicate that the two
genotypes also respond similarly to the bitter taste of the nicotine,
further supporting the specificity of PKC on ethanol consumption.
Nosepoke test
Preliminary analyses of efficiency ratio and conditioned response
data indicated that there were no significant effects of gender.
Therefore, subsequent analyses were performed on data collapsed across
gender. The mean number of days to criterion for phases 1-3 are listed
in Table 1. There were no significant differences between the genotypes for these variables, indicating that
the rate of acquisition of the nosepoke task for reward was equivalent
in both genotypes. Although the ability to withhold responses as
indicated by the curves of the efficiency ratios for both null mutant
and wild-type mice increased across the 10 sessions
(F(1,45) = 69.55; p < 0.0001) (Fig. 2A),
there was a significant main effect of genotype
(F(1,45) = 15.39; p < 0.0001) and a significant genotype by efficiency ratio interaction
(F(1,45) = 3.16; p < 0.001). This interaction is explained by the significant difference in
the slopes of the efficiency ratios of null mutant (0.0325 ± 0.005) and wild-type mice (0.048 ± 0.004)
(t48 = 2.609; p < 0.01). The slope of the efficiency ratio in the mutant mice was less
than that of the wild-type mice, and the efficiency ratio mean score on
day 10 was also lower in the mutant mice, reflecting the reduction in
behavioral control in PKC null mutant mice. A repeated measures
ANOVA of the percentage of conditioned responses across the 10 trials
demonstrated that the %CR curves did not differ between null mutant
and wild-type mice (p = 0.46) (Fig. 2B). Because this variable is a measure of the
ability of the mice to learn to respond to the auditory signal, this
result indicates that the impulsive behavior demonstrated by PKC
mutant mice was not caused by an inability to learn the conditioned
response but resulted from an inability to withhold their responses
during the preauditory time period.
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Figure 2.
Impulsivity as measured in a signaled-nosepoke
task was greater in PKC null mutant mice (n = 25) compared with wild-type control mice (n = 25).
A, The efficiency ratio, a measure of impulsivity, was
significantly decreased in mutant mice over 10 trials
(p < 0.0001), demonstrating their inability
to withhold their nosepoke responses for a food reward. Slopes of the
efficiency ratio curves were also significantly different between the
genotypes [i.e., mutants: 0.0325 ± 0.005; wild-type: 0.048 ± 0.004 (p < 0.01)]. B,
The ability to learn to respond to the auditory signal was not
different between PKC null mutant mice and wild-type controls,
indicating that performance by the mutant mice was not caused by a
learning deficit. This is represented by the %CR across the 10 trials.
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DISCUSSION |
The relationship between impulsivity and a susceptibility to high
levels of alcohol consumption has been reported in both animal (Poulos
et al., 1995; Logue et al., 1998) and human studies (Cloninger, 1987;
Heinz et al., 2001). Recently, Logue et al. (1998) reported a
significant genetic correlation in 13 inbred strains of mice between
impulsivity and ethanol consumption, suggesting that the same genetic
mechanisms regulate both behaviors. The results of the present study
indicate that PKC may be one genetic factor influencing the two
behaviors. Multiple effects of PKC isotypes might be expected because
of the role of the PKC gene family as a central regulator of numerous
intracellular functions, including phosphorylation of ligand-gated and
voltage-dependent ion channels, transcription factors, adenylate
cyclase, and calmodulin binding proteins (Mahoney and Huang, 1994).
This assumption is supported by recent investigations of
ethanol-related behaviors in mice lacking another PKC isotype, the
PKC null mutants, which in contrast to the PKC mutant mice have
increased initial sensitivity to ethanol and consume less
ethanol (Hodge et al., 1999).
The pleiotropic effects of PKC on impulsivity and ethanol
consumption as well as its effects on initial sensitivity and tolerance to ethanol, and baseline anxiety as reported previously (Harris et al.,
1995; Bowers et al., 1999, 2000a,b, 2001), may be caused by direct
effects of the enzyme but more likely results from the downstream
effects of PKC on other proteins that are important in the
expression of these behaviors. For example, ethanol potentiation of
GABAA receptor function is significantly
decreased in cerebellar tissue from PKC null mutant mice (Harris et
al., 1995), a brain region associated with the sedative effects of
ethanol (Spuhler et al., 1982). Null mutant mice also demonstrate
decreased initial sensitivity to the sedative effects of ethanol
compared with wild-type controls (Harris et al., 1995; Bowers et al.,
1999, 2000b). This implies that PKC indirectly regulates initial
sensitivity via phosphorylation of the GABAA
receptor. The interaction of PKC and the GABAA
receptor may also regulate increased ethanol consumption and
impulsivity observed in the present study; however, the interaction of
PKC with other neurotransmitter systems cannot be ruled out. Studies of
neurochemical pathways in rodent models of increased ethanol
consumption as well as numerous studies of alcohol abuse in humans have
shown that both increased alcohol consumption and impulsivity may be
the result of decreased serotonergic function (LeMarquand et al.,
1994a,b; Leyton et al., 2001). Specifically, PKC is involved in the
pathway directing agonist-induced downregulation of
5HT2 receptors (for review, see Roth et al.,
1998) and appears to be important for serotonin reuptake (Sakai et al.,
2000).
Inbred strain differences in mice have been reported for nicotine
preference/consumption, indicating that nicotine consumption is
genetically determined (Robinson et al., 1996). In addition, a genetic
relationship has been reported between alcohol and nicotine in humans
(Madden et al., 1997; True et al., 1999) and in rodents (de Fiebre and
Collins, 1993; Luo et al., 1994), suggesting that sensitivity to both
substances may be under the same genetic control. However, in the
present study, the increased preference for ethanol exhibited by the
null mutant mice did not generalize to nicotine. Therefore, PKC does
not appear to be a shared genetic factor in oral consumption of both
ethanol and nicotine. However, an evaluation of operant responding for
nicotine in these genotypes would more clearly address the issue of the
role of PKC in nicotine reinforcement.
In summary, PKC null mutant mice consume more ethanol and are more
impulsive than wild-type littermate controls, suggesting a pleiotropic
effect of the isotype on these two behaviors. However, it should be
noted that genetic background can influence responses in these null
mutant mice (Bowers et al., 1999); therefore, the results of the
present study are in the context of the C57BL/6 × 129/SvEvTac
mixed background. In addition to the increase in impulsivity observed
in the null mutant mice, their decreased initial sensitivity to ethanol
suggests that these mice may be a relevant model for elucidating
genetic regulation as well as neurochemical pathways involved in the
predisposition to alcoholism in some individuals.
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FOOTNOTES |
Received May 29, 2001; revised Aug. 14, 2001; accepted Aug. 16, 2001.
This work was supported by National Institutes of Health Grants
AA-11275 to B.J.B. and J.M.W., AA-03527 and AA-00141, and a
Research Career Award to J.M.W. We thank Michelle Bohl and Katy Elliott for their technical assistance in collecting data for the
ethanol consumption and impulsivity studies, and Jill Miyamoto for her
expertise in genotyping the mice.
Correspondence should be addressed to Barbara J. Bowers, Institute for
Behavioral Genetics, UCB 447, University of Colorado, Boulder, CO
80309. E-mail:bbowers{at}colorado.edu.
This article is published in
The Journal of Neuroscience, Rapid Communications Section,
which publishes brief, peer-reviewed papers online, not in print. Rapid
Communications are posted online approximately one month earlier than
they would appear if printed. They are listed in the Table of Contents
of the next open issue of JNeurosci. Cite this article as:
JNeurosci, 2001, 21:RC180 (1-5). The
publication date is the date of posting online at
www.jneurosci.org.
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REFERENCES |
-
Abeliovich A,
Paylor R,
Chen C,
Kim JJ,
Wehner JM,
Tonegawa S
(1993)
PKC mutant mice exhibit mild deficits in spatial and contextual learning.
Cell
75:1263-1271[Medline].
-
Belknap JK,
Crabbe JC,
Young ER
(1993)
Voluntary consumption of ethanol in 15 inbred mouse strains.
Psychopharmacology
112:503-510[Medline].
-
Bowers BJ,
Owen EH,
Collins AC,
Abeliovich A,
Tonegawa S,
Wehner JM
(1999)
Decreased ethanol sensitivity and tolerance development in -protein kinase C null mutant mice is dependent on genetic background.
Alcohol Clin Exp Res
23:387-397[Medline].
-
Bowers BJ,
Collins AC,
Tritto T,
Wehner JM
(2000a)
Mice lacking PKC exhibit decreased anxiety.
Behav Genet
30:111-121[Medline].
-
Bowers BJ,
Collins AC,
Wehner JM
(2000b)
Background genotype modulates the effects of -PKC on the development of rapid tolerance to ethanol-induced hypothermia.
Addict Biol
5:47-58.
-
Bowers BJ,
Elliott KJ,
Wehner JM
(2001)
Differential sensitivity to the anxiolytic effects of ethanol and flunitrazepam in PKC null mutant mice.
Pharmacol Biochem Behav
69:99-110[Medline].
-
Cloninger CR
(1987)
Neurogenetic adaptive mechanisms in alcoholism.
Science
236:410-416[Medline].
-
Daeppen JB,
Smith TL,
Danko GP,
Gordon L,
Landi NA,
Nurnberger JI,
Bucholz KK,
Raimo E,
Schuckit MA
(2000)
Clinical correlates of cigarette smoking and nicotine dependence in alcohol-dependent men and women. The Collaborative Study Group on the Genetics of Alcoholism.
Alcohol Alcohol
35:171-175[Abstract/Full Text].
-
de Fiebre CM,
Collins AC
(1993)
A comparison of the development of tolerance to ethanol and cross-tolerance to nicotine after chronic ethanol treatment in long- and short-sleep mice.
J Pharmacol Exp Ther
266:1398-1406[Abstract].
-
Finn PR,
Earlywine M,
Pihl RO
(1992)
Sensation seeking, stress reactivity, and alcohol dampening discriminate the density of a family history of alcoholism.
Alcohol Clin Exp Res
16:585-590[Medline].
-
Goldman D,
Lappalainen J,
Azaki N
(1996)
Direct analysis of candidate genes in impulsive behaviors.
Ciba Found Symp
194:139-154[Medline].
-
Grahame NJ,
Li T-K,
Lumeng L
(1999)
Selective breeding for high and low alcohol preference in mice.
Behav Genet
29:47-57[Medline].
-
Harris RA,
McQuilken SJ,
Paylor R,
Abeliovich A,
Tonegawa S,
Wehner JM
(1995)
Mutant mice lacking the isoform of protein kinase C show decreased behavioral actions of ethanol and altered function of -aminobutyrate type A receptors.
Proc Natl Acad Sci USA
92:3658-3662[Abstract].
-
Heinz A,
Mann K,
Weinberger DR,
Goldman D
(2001)
Seotonergic dysfunction, negative mood states, and response to alcohol.
Alcohol Clin Exp Res
25:487-495[Medline].
-
Hodge CW,
Mehmert KK,
Kelley SP,
McMahon T,
Haywood A,
Olive MF,
Wang D,
Sanchez-Perez AM,
Messing RO
(1999)
Supersensitivity to allosteric GABAA receptor modulators and alcohol in mice lacking PKC.
Nat Neurosci
2:997-1002[Medline].
-
Kushner MG,
Abrams K,
Borchardt C
(2000)
The relationship between anxiety disorders and alcohol use disorders: a review of major perspectives and findings.
Clin Psychol Rev
20:149-171[Medline].
-
LeMarquand D,
Pihl RO,
Benkelfat C
(1994a)
Serotonin and alcohol intake, abuse and dependence: clinical evidence.
Soc Biol Psychiatry
36:327-337.
-
LeMarquand D,
Pihl RO,
Benkelfat C
(1994b)
Serotonin and alcohol intake, abuse, and dependence: findings of animal studies.
Soc Biol Psychiatry
36:395-421.
-
Leyton M,
Okazawa H,
Diksic M,
Paris J,
Rosa P,
Mzengeza S,
Young SN,
Blier P,
Benkelfat C
(2001)
Brain regional
 -[11C] methyl-L-tryptophan trapping in impulsive subjects with borderline personality disorder.
Am J Psychiatry
158:775-782[Abstract/Full Text].-
Logue SF,
Swartz RJ,
Wehner JM
(1998)
Genetic correlation between performance on an appetitive-signaled nosepoke task and voluntary ethanol consumption.
Alcohol Clin Exp Res
22:1912-1920[Medline].
-
Luo Y,
Marks MJ,
Collins AC
(1994)
Genotype regulates the development of tolerance to ethanol and cross-tolerance to nicotine.
Alcohol
11:167-176[Medline].
-
Madden PAF,
Heath AC,
Martin NG
(1997)
Smoking and intoxication after alcohol challenge in women and men: genetic influences.
Alcohol Clin Exp Res
21:1732-1741[Medline].
-
Mahoney CW,
Huang K-P
(1994)
Molecular and catalytic properties of protein kinase C.
In: Protein kinase C (Kuo JF,
ed), pp 16-63. New York: Oxford UP.
-
Marks IM
(1986)
Genetics of fear and anxiety disorders.
Br J Psychiatry
149:406-418[Abstract].
-
Middaugh LD,
Kelley BM,
Bandy A-LE,
McGroarty KK
(1999)
Ethanol consumption by C57BL/6 mice: influence of gender and procedural variables.
Alcohol
17:175-183[Medline].
-
Newlin DB,
Thomson JB
(1991)
Chronic tolerance and sensitization to alcohol in sons of alcoholics.
Alcohol Clin Exp Res
15:399-405[Medline].
-
Peirce JL,
Derr R,
Shendure J,
Kolata T,
Silver LM
(1998)
A major influence of sex-specific loci on alcohol preference in C57Bl/6 and DBA/2 inbred mice.
Mamm Genome
9:942-948[Medline].
-
Poulos CX,
Le AD,
Parker JL
(1995)
Impulsivity predicts individual susceptibility to high levels of alcohol self-administration.
Behav Pharmacol
6:810-814[Medline].
-
Robinson SF,
Marks MJ,
Collins AC
(1996)
Inbred mouse strains vary in oral self-selection of nicotine.
Psychopharmacology
124:332-339[Medline].
-
Rodriguez LA,
Plomin R,
Blizard DA,
Jones BC,
McClearn GE
(1994)
Alcohol acceptance, preference, and sensitivity in mice. I. Quantitative genetic analysis using BxD recombinant inbred strains.
Alcohol Clin Exp Res
18:1416-1422[Medline].
-
Roth BL,
Berry SA,
Kroeze WK,
Willins DL,
Kristiansen K
(1998)
Serotonin 5-HT2A receptors: molecular biology and mechanisms of regulation.
Crit Rev Neurobiol
12:319-338[Medline].
-
Sakai N,
Kodama N,
Ohmori S,
Sasaki K,
Saito N
(2000)
Involvement of the actin cytoskeleton in the regulation of serotonin transporter (SET) activity: possible mechanism underlying SET regulation by protein kinase C.
Neurochem Int
36:567-579[Medline].
-
Schuckit MA
(1987)
Biological vulnerability to alcoholism.
J Consult Clin Psychol
55:301-309[Medline].
-
Schuckit MA
(1998)
Biological, psychological and environmental predictors of the alcoholism risk: a longitudinal study.
J Stud Alcohol
59:485-494[Medline].
-
Spuhler K,
Hoffer B,
Weiner N,
Palmer M
(1982)
Evidence for genetic correlation of hypnotic effects and cerebellar Purkinje neuron depression in response to ethanol in mice.
Pharmacol Biochem Biol
17:569-578.
-
True WR,
Xian H,
Scherrer JF,
Madden PAF,
Bucholz KK,
Heath AC,
Eisen SA,
Lyons MJ,
Goldberg J,
Tsuang M
(1999)
Common genetic vulnerability for nicotine and alcohol dependence in men.
Arch Gen Psychiatry
56:655-661[Medline].
-
Young SE,
Stallings MC,
Corley RP,
Krauter KS,
Hewitt JK
(2000)
Genetic and environmental influences on behavioral disinhibition.
Am J Med Genet
96:684-695[Medline].
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ABSTRACT
INTRODUCTION
