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The Journal of Neuroscience, November 1, 1999, 19(21):9550-9556
Dopamine D4 Receptor-Knock-Out Mice Exhibit Reduced Exploration
of Novel Stimuli
Stephanie C.
Dulawa1,
David K.
Grandy3,
Malcolm
J.
Low4,
Martin P.
Paulus2, and
Mark A.
Geyer1, 2
Departments of 1 Neuroscience, and
2 Psychiatry, University of California at San Diego, La
Jolla, California 92093-0804, 3 Department of Physiology
and Pharmacology, and 4 Vollum Institute, Oregon Health
Sciences University, Portland, Oregon 97201
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ABSTRACT |
The involvement of dopamine neurotransmission in behavioral
responses to novelty is suggested by reports that reward is related to
increased dopamine activity, that dopamine modulates exploratory behavior in animals, and that Parkinson's disease patients report diminished responses to novelty. Some studies have reported that polymorphisms of the human dopamine D4 receptor (D4R) gene are associated with personality inventory measures of the trait called "novelty-seeking". To explore a potential role for the D4R in behavioral responses to novelty, we evaluated D4R-knock-out (D4R /) and wild-type (D4R+/+) mice in three approach-avoidance paradigms: the
open field, emergence, and novel object tests. These three paradigms
differ in the degree to which they elicit approach, or exploratory
behavior, and avoidance, or anxiety-related behavior. Thus, we used
these three tests to determine whether the D4R primarily influences the
exploratory or the anxious component of responses to
approach-avoidance conflicts. D4R/ mice were significantly less
behaviorally responsive to novelty than D4R+/+ mice in all three tests.
The largest phenotypic differences were observed in the novel object
test, which maximizes approach behavior, and the smallest phenotypic
differences were found in the open field test, which maximizes
avoidance behavior. Hence, D4R/ mice exhibit reductions in
behavioral responses to novelty, reflecting a decrease in
novelty-related exploration.
Key words:
novelty; D4 receptor; exploration; approach-avoidance; mice; anxiety; open field
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INTRODUCTION |
Much interest in the dopamine D4
receptor (D4R) has been generated recently because of reports that
specific tandem repeat polymorphisms of the human D4R gene correlate
with higher than average novelty-seeking scores on questionnaires
(Benjamin et al., 1996 ; Ebstein et al., 1996), although others have
been unable to replicate these findings (Malhotra et al., 1996;
Vandenbergh et al., 1997; Kuhn et al., 1999). To examine a potential
role for the D4R in behavioral responses to novelty, D4R+/+ and
D4R/ mice (Rubinstein et al., 1997) were assessed in three
approach-avoidance conflicts: the open field, emergence, and novel
object tests.
Novel stimuli, such as unfamiliar environments or objects, are
theorized to create conflict in rodents by concurrently evoking both
approach and avoidance behaviors (Montgomery, 1955; Dember, 1956;
Welker, 1957; Berlyne, 1960). Approach behavior or "exploration" reflects an animal's tendency to explore novel stimuli or
environments, whereas avoidance behavior or "anxiety-related
behavior" is thought to reflect an animal's fear of novelty. Because
novel stimuli elicit this approach-avoidance conflict, phenotypic
differences in behavioral responses to novelty cannot be interpreted as
indicative of changes in either exploratory drive or anxiety unless the
relative contributions of these competing tendencies is manipulated by varying the testing environment. The three tests used here were selected based on their ability to elicit these two behavioral dimensions differentially in rodents by providing varying degrees of
stimulus novelty and escape potential within the same environmental context. Comparisons of effect sizes observed across these three tests
can provide converging evidence of a phenotypic difference in either
approach or avoidance responses to novelty.
The open field test, which is the most anxiety-provoking of the three
tests, is thought to induce moderate anxiety (Welker, 1957; Hennessy et
al., 1979; Belzung, 1992) by confronting rodents with a novel
environment with no possibility of escape. By contrast, the emergence
test is a free exploration paradigm designed to reduce anxiety by
providing a safe enclosure within the open field in order to assess
approach or exploratory behavior in rodents (Welker, 1957; Misslin and
Cigrand, 1986). The novel object test (Belzung, 1992; Renner et
al., 1992) is another free exploration paradigm, which elicits
the most approach or exploration of the three tests by presenting
animals with the most novel stimuli (Berlyne, 1960; Fowler, 1965;
Berlyne and Slater, 1969; Dutch and Brown, 1971) in a familiar
environmental context. By comparing the effect sizes of phenotypic
differences in the three tests, it is possible to disentangle the
potential role of the D4R in exploratory behavior from its potential
role in anxiety-related behavior (Montgomery, 1955).
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MATERIALS AND METHODS |
Subjects
D4R+/+ and D4R/ mice (Oregon Health Sciences University,
Portland, OR) were 8-week-old F2s (C57BL/6J × 129Sv/Ola) that
weighed 20-40 gm. Mice were maintained on a 12 hr light/dark schedule (lights off at 7:00 A.M.) and were housed in groups of four to five
with same-type mice. Food and water were provided ad
libitum. Behavioral testing occurred during the dark phase between
8:00 A.M. and 6:00 P.M. Two D4R+/+ and three D4R/ male mice were killed after the emergence test because of lacerations from
fighting with cage-mates, and thus were not assessed in the novel
object test. All animal testing was conducted in accord with the
National Institutes of Health laboratory animal care guidelines and
with local animal care committee approval. No sex differences were predicted; mice of either sex were used as available for all tests.
Apparatus and procedures
Motor activity was quantified using the Polytrack video system
(San Diego Instruments, San Diego, CA). A video camera mounted centrally, 160 cm above the apparatus, monitored four separate 40-cm-long × 40-cm-wide × 37-cm-high white Plexiglas open
fields, with one mouse in each field. A computer program was used to
overlay grid lines that defined separate regions within each open
field. Paths taken by each mouse were stored permanently as
x-y coordinate sequences. Overall locomotor
activity was assessed as the total number of crossings between regions
of the open field during the test session.
Open field test. D4R+/+ (n = 18) and
D4R/ (n = 21) male mice were subjects. This cohort
of mice was used only in the open field test. Mice were tested for 30 min on 3 separate test days, each separated by 1 d of rest. The
computer defined grid lines that divided each open field into nine
separate regions: four corner regions, four wall or "side" regions,
and one square region in the center, with each of four lines being 10 cm from each wall (Fig. 1). We assessed
the number of entries into the center, and the total time spent in the
center. Overall motor activity was quantified as the total number of
crossings between the nine regions of the open field.
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Figure 1.
Regions within the open field apparatus for the
open field, emergence, and novel object tests formed by computer
overlaid grid lines (as viewed from above). The gray
rectangle in the emergence test represents the cylinder; the
gray circle in the novel object test represents the
novel cup.
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Emergence test. D4R+/+ (28 female, 33 male) and D4R/ (29 female, 46 male) mice were subjects. Each open field contained an
aluminum cylinder (10-cm-deep and 6.5 cm in diameter) located lengthwise along one wall, with the open end 10 cm from the corner. Mice were placed into the cylinder and tested for 15 min. A trained observer blind to genotype scored the following behaviors: the latency
to leave the cylinder, defined as placement of all four paws into the
open field; the number of entries into the cylinder with the initial
placement counting as an entry; the total time spent inside the
cylinder; and the mean time in the cylinder per entry (MTIC). The
computer defined grid lines in the same manner as described for the
open field test (Fig. 1). Overall motor activity was quantified as the
total number of crossings between the nine regions of the open field.
Novel object test. After being used in the emergence test,
the same mice [D4R+/+ (28 female, 33 male) and D4R/ (29 female, 46 male)] mice were tested in the novel object test. Mice had been
familiarized with the open field during the emergence test. Fourteen
days later, mice were placed into the open field for 30 min. Then, a
novel paper cup measuring 9.5 cm in height and 7.5 cm in diameter at
the rim was placed upside-down into the center of each open field and
was secured to the floor with tape placed inside the cups. Mice were
tested for an additional 30 min with the cup. The computer defined grid
lines that divided each open field into five separate regions: one
circular region in the center with a diameter of 18 cm and a
surrounding region that was divided into fourths by gridlines that
extended from the middle of each wall to the edge of the center region
(Fig. 1). The percentage of entries made into the center, the
percentage of time spent in the center, and overall locomotor activity
were assessed by an automated video-tracking system (Fig. 1). Overall motor activity was quantified as the total number of crossings between
the five regions of the open field.
Statistical analysis
Open field test. Two-factor ANOVAs with genotype as a
between-subjects factor and day as a within-subjects factor were
applied to three measures: the total time spent in the center, the
number of entries into the center, and overall motor activity. A
significant effect of day on overall motor activity was analyzed with
post hoc one-way ANOVAs, with  levels adjusted appropriately.
Emergence test. Two-factor ANOVAs with genotype and sex as
between-subjects factors were applied to each of five measures: latency
to leave the cylinder, number of entries into the cylinder, total time
spent inside the cylinder, MTIC, and overall motor activity.
Significant interactions were analyzed with post hoc one-way
ANOVAs, with levels adjusted appropriately.
Novel object test. Three-factor ANOVAs with genotype and sex
as between-subjects factors and environmental condition (with vs
without cup) as a within-subjects factor were applied to three different measures: percentage of entries into the center, percentage of time spent in the center, and overall locomotor activity.
Significant interactions were analyzed using post hoc ANOVAs
with adjusted levels.
When significant phenotypic differences in locomotor activity were
observed in any of the three test paradigms, ANCOVAs were applied to
exploratory measures with locomotor activity as a covariate. Remaining
significant differences between genotypes indicate independence between
measures of locomotor activity and exploration. Effect size (ES) was
calculated as the difference between means divided by the square root
of the error mean square of the F ratio (Cohen, 1988) for
all exploratory measures with phenotypic differences.
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RESULTS |
Open field test
Mice were tested on 3 separate days in the open field, a forced
exploration paradigm (Welker, 1957; Adams and Geyer, 1985; Belzung,
1992) in which escape from novelty is impossible. D4R+/+ and D4R/
mice showed no differences in locomotor activity over the 3 d of
testing (Fig. 2). Both genotypes
exhibited locomotor habituation over time, showing reduced levels of
activity on the second (F(1,76) = 6.52; p < 0.01) and third
(F(1,76) = 6.04; p < 0.02) days relative to the first day (Table
1). D4R/ mice exhibited reduced
behavioral responses to novelty relative to D4R+/+ mice, as indicated
by fewer entries into the center
(F(1,111) = 4.4; p < 0.04), and a trend to spend less time in the center (F(1,111) = 3.14; p = 0.08). The novelty of the center of the open field diminishes over time
(Fowler, 1965), but its anxiogenic properties do not (Adams and Geyer,
1985). Therefore, entries into the center primarily reflect exploratory
behavior on the first day of open field testing, but primarily reflect
anxiety-related behavior after repeated testing. We assessed the effect
size of the phenotypic difference in center entries for each day. The largest effect size was observed on the novel day of testing, and
decreased each subsequent day: day one (ES = 0.7), day two (ES = 0.4), and day three (ES = 0.1). The phenotypic
difference in center entries on day one primarily reflects a reduction
in approach or exploratory behavior in D4R/ mice (ES = 0.7),
but on day three primarily reflects a reduction in anxiety in
D4R/ mice (ES = 0.1).
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Figure 2.
Motor activity. Total locomotor activity in the
emergence, novel object, and open field tests is shown for D4R+/+ and
D4R/ mice. Values are means ± SEM. *p < 0.05 versus D4R+/+ group with ANOVA.
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We applied an ANCOVA to center entries, with locomotor activity as a
covariate, to assess whether phenotypic differences in behavioral
responses to novelty and locomotor activity were independent. In the
present experiment, ANCOVA revealed that the decreases in center
entries exhibited by D4R/ mice remained significant, even after
accounting for the variance associated with the levels of locomotor
activity. Thus, D4R/ mice were less behaviorally responsive to
novelty than D4R+/+ mice in 3 d of open field testing.
Emergence test
Mice were assessed in the emergence test, a free exploration
paradigm (Welker, 1957; Adams and Geyer, 1985; Belzung and Le Pape,
1994) in which animals can explore the open field or retreat into a
cylinder. D4R/ mice were less behaviorally responsive to the novel
environment than D4R+/+ mice. Relative to D4R+/+ mice, D4R/ mice
had significantly longer latencies to emerge from the cylinder
(F(1,132) = 4.62; p < 0.03), spent significantly more total time inside the cylinder
(F(1,132) = 29.81; p < 0.005), made fewer entries into the cylinder
(F(1,132) = 12.35; p < 0.002), and had significantly larger MTIC values
(F(1,132) = 6.12; p < 0.02) (Fig. 3). Additionally, a
significant genotype × sex interaction with respect to entries
into the cylinder was indicated. Post hoc tests showed that
D4R+/+ female mice made more transitions than D4R+/+ male mice
(F(1,60) = 21.57; p < 0.0001) and D4R/ female mice
(F(1,56) = 15.43; p < 0.0003), indicating that the reduction in entries into the cylinder
exhibited by D4R/ mice was caused by female mice (Fig.
4). D4R/ mice were also less active
overall than D4R+/+ mice (F(1,132) = 8.61; p < 0.01) (Fig. 2). Female mice were less active
overall (F(1,132) = 5.04;
p < 0.03) (510.0 ± 27.4 vs 583.8 ± 23.5)
and spent more time in the cylinder
(F(1,132) = 9.16; p < 0.004) than male mice, but these effects did not interact with
genotype.
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Figure 3.
Emergence test. Exploratory measures of the
emergence test are shown for D4R+/+ (n = 61) and
D4R/ mice (n = 75). The latency to emerge from
the cylinder in seconds (a), the total time spent
in the cylinder in seconds (b), the total number
of entries into the cylinder (c), and the MTIC in
seconds (d) are shown for both genotypes. Values
are means ± SEM. *p < 0.05 versus D4R+/+
group with ANOVA; #p < 0.05 versus D4R+/+ group
with ANCOVA.
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Figure 4.
Cylinder entries: sex differences. The number of
entries into the cylinder during the emergence test is shown for male
D4R+/+ (n = 31), male D4R/
(n = 43), female D4R+/+ (n = 28), and female D4R/ mice (n = 29). Values are
means ± SEM. *p < 0.05 versus female D4R+/+
group with ANOVA; +p < 0.05 versus male D4R+/+
group with ANOVA.
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Appropriate ANCOVAs confirmed that the phenotypic differences for total
time spent in (ES = 0.8) and number of entries into the cylinder
(ES = 0.5) remained significant, independent of the level of
locomotor activity. In contrast, the phenotypic differences for latency
to emerge and for MTIC values were no longer significant, indicating
that the differences in these measures were directly related to motor
activity levels. Additionally, the main effect of sex on time spent in
the cylinder was also dependent on the differences in locomotor
activity. Thus, D4R/ mice exhibited reduced behavioral responses to
novelty compared to D4R+/+ mice, as indicated by the measures of time
spent in the cylinder and number of entries into the cylinder.
Novel object test
Mice were tested in the novel object test, a free exploration
paradigm (Belzung, 1992; Renner et al., 1992; Belzung and Le Pape,
1994) that provides animals the opportunity to explore a novel object
in a non-threatening and familiar environment. Both genotypes spent a
higher percentage of time and made a higher percentage of entries into
the center after introduction of the cup, confirming that the novel cup
elicited approach behavior. Both genotypes made comparable increases in
the percentage of center entries after introduction of the cup.
Nevertheless, D4R/ mice were less behaviorally responsive to the
novel cup than D4R+/+ mice (Fig. 5),
because D4R/ mice made a smaller increase in the percentage of time
spent in the center after introduction of the cup than D4R+/+ mice
(F(1,127) = 19.24; p < 0.0001). Post hoc tests indicated that, although both
genotypes spent significantly more time in the center after
introduction of the cup, D4R/ mice spent significantly less percent
time in the center than D4R+/+ mice during this condition
(F(1,71) = 58.47; p < 0.0001). No interactions of sex and genotype were evident for these
measures. Analyses using raw scores yielded the same conclusions as
analyses using percentage scores for all measures. D4R/ mice were
also less active overall than D4R+/+ mice
(F(1,127) = 12.18; p < 0.0001) (Fig. 2). A sex difference in which female mice engaged in
more locomotor activity than male mice was also observed
(F(1,127) = 6.19; p < 0.01) (1079.7 ± 53.6 vs 906.3 ± 42.0), but no interaction of sex and genotype was found.
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Figure 5.
Novel object test. The percentage of time spent in
the center region (a) and the percentage of
center entries (b) are shown for D4R+/+
(n = 59) and D4R/ mice (n = 72) for both environmental conditions of the novel object test. Values
are means ± SEM. *p < 0.05 genotype × condition interaction with ANOVA; #p < 0.05 genotype × condition with ANCOVA.
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Appropriate ANCOVAs testing for any relationship between locomotor
activity and behavioral responses to novelty revealed that the increase
in percentage of time spent in the center, after introduction of the
cup, remained significantly decreased in D4R/ mice (ES = 1.4).
Thus, D4R/ mice exhibited independent reductions in locomotor
activity and behavioral responses to novelty relative to D4R+/+ mice in
the novel object test.
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DISCUSSION |
Here we report that mice lacking the D4R exhibit reduced
behavioral responses to novelty. In the open field test, D4R/ mice made fewer entries into the center, but did not differ in overall levels of activity compared to D4R+/+ mice. In the emergence test, D4R/ mice spent more time in the cylinder and made fewer entries into the cylinder than D4R+/+ mice. In the novel object test, D4R/
mice made a smaller increase in percentage of time spent in the center
after introduction of the cup relative to D4R+/+ mice. We have also
replicated these basic findings in an independent group of mice
(n = 61) (data not shown). These three tests were used
to explore the extent to which changes in exploratory drive or anxiety
accounted for the phenotypic differences in response to
approach-avoidance conflicts. Differences in approach or exploratory behavior appear to account for much of the behavioral phenotype, rather
than avoidance or anxiety-related behaviors, because the effect size
was largest in the novel object test (ES = 1.4), intermediate in
the emergence test (ES = 0.8, 0.5), and smallest in the open field
test (ES = 0.1). The effect size for center entries on day three
of the open field test was used for comparison because this measure
primarily reflects avoidance or anxiety-related behavior, whereas
center entries on day one are more indicative of approach or
exploratory behavior. We also assessed effect sizes without including
females to avoid any confound of sex, because only males were used in
the repeated open field test. A similar pattern of effect sizes
resulted for the novel object (ES = 1.5), emergence (ES = 0.8, 0.1), and open field tests (ES = 0.1). Thus, compared to
D4R+/+ mice, D4R/ mice exhibited the largest reductions in behavioral responses to novelty in the test that is maximally sensitive
to approach behaviors (the novel object test), and the smallest
reductions in the test that is most reflective of avoidance behavior
(the open field test).
Our hypothesis that the D4R is involved in modulating behavioral
responses to novelty in mice derived from observations of an
association between polymorphisms of the D4R gene and personality inventory measures of the trait called novelty-seeking (Benjamin et
al., 1996; Ebstein et al., 1996). Our finding that knock-out of the D4R
results in diminished behavioral responses to novelty in mice is
consistent with the hypothesis that a lack of D4R function may lead to
decreased novelty-seeking in humans. A direct link, however, cannot be
made between the present results and the findings of the human
association studies (Benjamin et al., 1996; Ebstein et al., 1996),
because mice were either wild-type or D4R-deficient, whereas the human
subjects possessed different D4R alleles for which there is evidence
for varying function (Asghari et al., 1995). A null allele for the D4R
has been reported to occur in 2% of the general population (Nothen et
al., 1994). Comparing the novelty-seeking trait in subjects with the
null D4R allele to those with functional alleles could directly test
the hypothesis that lack of function of the D4R is associated with
diminished novelty-seeking in humans. The same D4R alleles associated
with novelty-seeking have recently been associated with behavioral disorders suggested to be related to novelty-seeking, such as drug
abuse (Kotler et al., 1997; Shields et al., 1998), pathological gambling (de Castro et al., 1997), and attention deficit hyperactivity disorder (LaHoste et al., 1996; Faraone et al., 1999). Further knowledge regarding the functional role of the D4R in behavioral responses to novelty could be an important step toward understanding the neurobiology of these disorders.
Mice lacking the D4R exhibited modest reductions in locomotor activity
in the open field (nonsignificant), emergence, and novel object tests
that were independent from the decreases in behavioral responses to
novelty, as revealed by ANCOVA. This decrease in locomotor activity
does not appear to result from a gross motor impairment, because
D4R/ mice have been reported to outperform D4R+/+ mice on the
rotarod and are supersensitive to the locomotor-activating effects of
ethanol, cocaine, and methamphetamine (Rubinstein et al., 1997). It has
been widely reported that the vulnerability of rats to drugs of abuse
can be predicted by their locomotor response to a novel environment
(Hooks et al., 1991, 1994), with high responders to novelty acquiring
amphetamine self-administration more readily (Piazza et al., 1989) and
exhibiting greater behavioral activation in response to amphetamine
(Hooks and Kalivas, 1994). One might predict that because D4R/ mice
exhibit less locomotor activity in a novel environment, they would show
less behavioral activation to drugs of abuse than D4R+/+ mice. The
supersensitivity of D4R/ mice to the locomotor activation produced
by ethanol, cocaine, and methamphetamine is thus surprising.
Phenotypes exhibited by knock-out mice of a mixed genetic background
can result from the introduction of background genes linked to the
mutated gene, rather than from the mutation itself. The present
D4R/ mice were generated using 129Sv/Ola stem cells crossed onto a
C57BL/6 background (Rubinstein et al., 1997). The 129Sv/Ola strain
performs normally relative to C57BL/6 mice in the open field test, the
Morris water maze, the plus maze, and on coordination tests (Montkowski
et al., 1997). In addition, 129Sv/Ola mice spend more time in the
center of a novel open field than C57BL/6 mice (Montkowski et al.,
1997), suggesting that the decrease in behavioral responses to novelty
exhibited by D4R/ mice is not caused by 129Sv/Ola background genes.
A priori hypotheses reduce the likelihood of false positives
when characterizing knock-out mice on a mixed background. The present
experiments were undertaken to test the hypothesis the D4R is involved
in modulating behavioral responses to novelty. Although it is
conceivable that the reduction in behavioral responses to novelty
observed in the D4R/ mice results from 129Sv/Ola background genes,
the observed phenotype is most likely caused by lack of the D4R. It
will be important to confirm these findings in congenic strains of
D4R+/+ and D4R/ mice.
Differences in dopamine neurotransmission in D4R/ mice are
localized to brain areas that could mediate the observed reductions in
behavioral responses to novelty. Although dopaminergic neurons of the
substantia nigra provide most of the dopaminergic projections to the
dorsal striatum, these neurons do not express D4Rs. Rather, D4Rs are
densely localized on glutamatergic pyramidal cells of frontal cortex
(Mrzljak et al., 1996; Ariano et al., 1997; Rubinstein et al., 1997)
that project to the dorsal striatum and the substantia nigra (Carter,
1982). The stimulation of nigrostriatal nerve terminals (Westerink et
al., 1992) in the dorsal striatum or of nigral neurons by glutamate
induces dopamine release (Overton and Clark, 1992). Accordingly,
dopamine synthesis and its conversion to DOPAC are increased in the
dorsal striatum of D4R/ mice (Rubinstein et al., 1997). Thus,
frontal cortical D4Rs may alter the activity of nigrostriatal dopamine
neurons by modulating the release of glutamate onto these neurons.
Furthermore, D4Rs in the frontal cortex are likely to be under
substantial influence of both noradrenergic inputs and dopaminergic
inputs, because dopamine is only fivefold more potent at this receptor
than epinephrine and norepinephrine, whereas dopamine is >100-fold
more potent at D2 receptors than epinephrine and norepinephrine (Lanau
et al., 1997).
Although effects of sex were neither predicted nor systematically
studied in the present experiments, some sex differences in behavior
were found. Female mice were more active overall than males in the
novel object test, which is consistent with numerous reports that
female mice are more active than male mice in many testing situations
(Norton, 1977). However, in the emergence test, females were less
active than males and spent more time in the cylinder than males,
although an ANCOVA showed that these two effects were related. Only one
interaction of genotype and sex was observed, in which female but not
male D4R/ mice made fewer entries into the cylinder than D4R+/+
mice in the emergence test. In both humans and rats, the modulation of
the mesostriatal dopamine system and related behaviors by estrogen has
been reported (Van Hartesveldt and Joyce, 1986), however, the human D4R
association studies on novelty seeking have not reported gender effects
(Benjamin et al., 1996; Ebstein et al., 1996; LaHoste et al., 1996;
Kotler et al., 1997; de Castro et al., 1997; Shields et al., 1998;
Faraone et al., 1999). Similarly, the important phenotypic differences observed in the present experiments did not interact significantly with
the sex differences.
Our findings support the hypothesis positing a functional role for the
D4R in behavioral responses to novelty. These results complement human
genetic association studies implicating D4R polymorphisms in naturally
occurring variations in the personality trait known as novelty seeking.
Although it cannot be concluded that D4R-deficient mice are without
abnormalities with regard to avoidance or anxiety-related behaviors,
the present results are best explained by a reduction in approach or
exploratory behavior. In conclusion, the D4R plays a role in modulating
approach-avoidance responses in general and novelty-related
exploration in particular.
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FOOTNOTES |
Received Aug. 3, 1999; accepted Aug. 4, 1999.
This work was supported by the National Institute on Drug Abuse (NIDA)
(Grants R01DA11277, R02DA02925, and R21DA09620), the National Alliance
for Research on Schizophrenia and Depression, and the United States
Veterans Affairs and VISN22 Mental Illness Research, Education, and
Clinical Center. S.C.D. was supported by a minority supplement from
NIDA (R02DA02925). M.A.G. holds an equity interest in San Diego
Instruments, Inc. We thank Dr. Lisa Gold for advice regarding
behavioral tests, Dr. Athina Markou for helpful comments on this
manuscript, and both Jennifer Larson and Elizabeth Lutz for technical assistance.
Correspondence should be addressed to Dr. Mark A. Geyer, Department of
Psychiatry 0804, University of California at San Diego, 9500 Gilman
Drive, La Jolla, CA 92093-0804. E-mail: mgeyer{at}ucsd.edu.
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ABSTRACT
INTRODUCTION
