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The Journal of Neuroscience, 2002, 22:RC208:1-6
RAPID COMMUNICATION
Voluntary Alcohol Consumption Is Controlled via the Neuropeptide
Y Y1 Receptor
Todd E.
Thiele1,
Ming
Teng
Koh2, and
Thierry
Pedrazzini3
1 Department of Psychology, University of North
Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3270, 2 Department of Psychology and the Alcohol and Drug Abuse
Institute, University of Washington, Seattle, Washington 98195, and
3 Division of Hypertension, University of Lausanne Medical
School, CH-1011 Lausanne, Switzerland
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ABSTRACT |
We have shown previously that voluntary ethanol consumption and
resistance to ethanol-induced sedation are inversely related to
neuropeptide Y (NPY) levels in NPY-knock-out
(NPY /) and NPY-overexpressing mice. In the
present report, we studied knock-out mice completely lacking the NPY Y1
receptor (Y1/) to further characterize the role
of the NPY system in ethanol consumption and neurobiological responses
to this drug. Here we report that male Y1/ mice
showed increased consumption of solutions containing 3, 6, and 10%
(v/v) ethanol when compared with wild-type (Y1+/+)
control mice. Female Y1/ mice showed increased
consumption of a 10% ethanol solution. In contrast,
Y1/ mice showed normal consumption of solutions
containing either sucrose or quinine. Relative to
Y1+/+ mice, male Y1/ mice
were found to be less sensitive to the sedative effects of 3.5 and 4.0 gm/kg ethanol as measured by more rapid recovery from
ethanol-induced sleep, although plasma ethanol levels did not differ
significantly between the genotypes. Finally, male Y1/ mice showed normal ethanol-induced ataxia on
the rotarod test after administration of a 2.5 gm/kg dose. These data
suggest that the NPY Y1 receptor regulates voluntary ethanol
consumption and some of the intoxicating effects caused by
administration of ethanol.
Key words:
alcohol consumption; sedation; NPY; receptor; knock-out; ataxia
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INTRODUCTION |
Neuropeptide
Y (NPY) is a 36 amino acid neurotransmitter that is widely distributed
throughout the nervous system (Dumont et al., 1992 ; Colmer and
Wahlestedt, 1993). NPY has been implicated in the control of food
intake (Clark et al., 1984; Levine and Morley, 1984), cerebrocortical
excitability (Woldbye et al., 1996, 1997), cardiovascular homeostasis
(Pedrazzini et al., 1998), and in the integration of emotional behavior
(Heilig et al., 1993; Heilig and Widerlov, 1995). Recent evidence
suggests that NPY is also involved with neurobiological responses to
ethanol. Rats that were selectively bred for alcohol preference have
altered levels of NPY in several brain regions compared with
alcohol-nonpreferring rats (Ehlers et al., 1998; Hwang et al., 1999),
and genetic linkage analysis of alcohol-preferring rats identified a
chromosomal region that includes the NPY gene (Carr et al., 1998).
Voluntary ethanol consumption and resistance to the intoxicating
effects of ethanol have been found to be inversely related to NPY
levels in knock-out and transgenic mice (Thiele et al., 1998, 2000a),
central infusion of exogenous NPY has been shown to modulate ethanol
drinking in rats (Badia-Elder et al., 2001a; Kelley et al., 2001), and
recent evidence indicates that the NPY system may modulate ethanol
consumption and seizure during withdrawal from ethanol in humans
(Kauhanen et al., 2000; Ilveskoski et al., 2001; Okubo and Harada,
2001). However, the NPY receptor(s) that mediate neurobiological
responses to ethanol and ethanol consumption have not been clearly identified.
In the mouse, NPY acts through at least five receptor subtypes, namely
the Y1, Y2, Y4, Y5, and Y6 receptors, all of which couple to
heterotrimeric G-proteins that inhibit production of cAMP
(Palmiter et al., 1998). The Y1 receptor has been identified in several
brain regions that are involved with neurobiological responses to
ethanol, including the hippocampus, the hypothalamus, and the amygdala
(Ryabinin et al., 1997; Naveilhan et al., 1998). Therefore, we studied
alcohol consumption by Y1/ mice, which
completely lack Y1 receptor expression as a result of targeted gene
disruption (Pedrazzini et al., 1998), and by normal
Y1+/+ mice.
Y1/ mice grow and reproduce at normal
rates despite slightly diminished daily food intake and a reduced
refeeding response to starvation. However, these animals develop
late-onset obesity because of low energy expenditure (Pedrazzini
et al., 1998). We predicted that Y1/
mice would display ethanol-associated phenotypes similar to
NPY/ mice, and thus consume
significantly more ethanol and show resistance to the intoxicating
effects of ethanol relative to wild-type mice.
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MATERIALS AND METHODS |
Animals. Generation of the
Y1/ mice has been described previously
(Pedrazzini et al., 1998). Starting with mice from the original population (Pedrazzini et al., 1998),
Y1/ mice were backcrossed for seven
generations into a C57BL/6J background and were then bred with
wild-type C57BL/6J mice to obtain heterozygote (Y1+/) knock-outs. Nonlittermate
heterozygous mice were then bred, and F2 mice
from this cross yielded Y1/ mice and
Y1+/+ mice. Littermate mice and their
immediate offspring were used in the present studies. Each study
described below used mice that were 8-14 weeks of age, before the
onset of obesity. Mice were individually housed in plastic mouse cages
with ad libitum access to standard rodent chow (Teklad;
Harlan, Madison, WI) and water throughout the experiments. The colony
room was maintained at ~22°C with a 12 hr light/dark cycle. All
procedures used in the present research were in compliance with
National Institutes of Health guidelines, and the protocols were
approved by the University of Washington Animal Care Committee.
Alcohol intake test. Throughout the experiments, fluid
intake, food intake, and body weight measures were assessed every
2 d. Y1/ mice (male,
n = 15; female, n = 10) and
Y1+/+ mice (male, n = 11;
female, n = 12) were habituated in their home cage to
drinking from two bottles containing plain water over 6 d. Mice
were then given 24 hr access to two bottles, one containing plain water
and the other containing ethanol in water. The concentration of ethanol
(v/v) was increased every 8 d; mice received 3%, 6%, and finally
10% ethanol over the course of the experiment. The positions of the
bottles were changed every 2 d to control for position
preferences. Average ethanol consumption per day was obtained for each
ethanol concentration. To obtain a measure of ethanol consumption that
corrected for individual differences in mouse size, grams of ethanol
consumed per killigram of body weight per day were calculated for each
mouse. As a measure of relative ethanol preference, an ethanol
preference ratio was calculated at the 10% ethanol concentration by
dividing total ethanol solution consumed by total fluid (ethanol plus
water) consumption. Two-way 2 × 3 (genotype × concentration) and 2 × 4 (genotype × trial)
repeated-measures ANOVAs were used for statistical examination
of the data.
Sucrose and quinine consumption test. Approximately 2 weeks
after ethanol consumption testing, mice (same as above) were given plain water in one bottle and sucrose or quinine in the other bottle.
The compounds were presented in the following order: sucrose solutions
(1.70 and 4.25%) followed by quinine solutions (0.03 mM and 0.10 mM). Mice had
48 hr of access to each solution, and the position of the solution was
counterbalanced between animals. Milliliters of solution consumed per
killigram of body weight per day were calculated for each mouse.
The data collected with each taste solution were analyzed separately
with two-way 2 × 2 (genotype × concentration)
repeated-measures ANOVAs.
Test for sensitivity to ethanol-induced sedation. Naive male
Y1/ (n = 13) and
Y1+/+ (n = 11) mice were
removed from their home cage and given an intraperitoneal injection of
ethanol [3.5 gm/kg; 20% (w/v) mixed in isotonic saline]. At the
onset of ethanol-induced sedation, each mouse was placed on its back
into a plastic U-shaped trough. The time (in minutes) that elapsed
between the ethanol injection and when the mouse could right itself
onto all four paws three times within a 30 sec interval was used as the
index of time to regain the righting reflex. Approximately 2 weeks
after the first injection, the same mice were again given an
intraperitoneal injection of ethanol [4.0 gm/kg; 20% (w/v) mixed in
isotonic saline], and the time to regain the righting reflex was
assessed. These data were analyzed with two-way 2 × 2 (genotype × concentration) repeated-measures ANOVAs.
Accelerating rotarod test. The rotarod test was used to
assess sensitivity to drug-induced motor incoordination (herein
referred to as ataxia) with naive mice. The rotarod apparatus (Ugo
Basile Biological Research, Varese, Italy) consisted of a 3 cm diameter horizontal rotating rod divided into five 6 cm sections by tan acrylic
disks. The rod was rotated by a motor that accelerated from 4 to 40 rpm
over the course of 5 min. For each trial, the mouse was placed on the
stationary rod, which was then rotated until the mouse fell. On days
1-3, mice were given three practice trials separated by 1 min. On days
4-5, mice were given two practice trials, and then a third trial that
was immediately preceded by an intraperitoneal injection of saline to
habituate them to the injection procedures. On day 6, mice were given
two practice trails. The third trial served as the critical test and
was preceded by an intraperitoneal injection of ethanol [2.5 gm/kg;
20% (w/v) mixed in isotonic saline]. Latency to fall (in seconds) on
the test trial was recorded as the measure of sensitivity to
ethanol-induced ataxia.
Plasma ethanol concentrations. Male
Y1/ (n = 12) and
Y1+/+ (n = 11) mice were
given an intraperitoneal injection of ethanol [3.5 gm/kg; 20% (w/v)
mixed in isotonic saline; the same low-dose concentration used during
sedation testing] and immediately returned to their home cages. At 1 hr after ethanol injection, one-half of the mice were rapidly
anesthetized with CO2 and decapitated for blood
collection. The remaining mice were anesthetized and decapitated 3 hr
after ethanol injection. Plasma ethanol levels were determined via
spectrophotometic methods (Enzymatic Determination of Alcohol Test;
Sigma, St. Louis, MO) and calculated as milligrams per deciliter. A
two-way 2 × 2 (genotype × time) multifactor ANOVA was used
to analyze the data.
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RESULTS |
Alcohol, sucrose, and quinine consumption tests
The male Y1/ mice consumed
significantly more of each ethanol solution than
Y1+/+ control mice (Fig.
1a,b). We expressed
consumption of 10% ethanol relative to total fluid consumption
(ethanol preference ratio). Both Y1/
and Y1+/+ mice preferred ethanol to water
(preference ratios of >0.50), a behavior that is characteristic of
C57BL/6 mice (Belknap et al., 1993). Strikingly, despite this high
basal consumption of ethanol by wild-type mice,
Y1/ mice still showed increased
ethanol consumption (Fig. 1c). There were no significant
differences between male Y1/ and
Y1+/+ mice, nor were there differences
over time, in measures of average body weight
(Y1/ mice, 26.0 ± 0.3 gm;
Y1+/+ mice, 26.5 ± 0.6 gm), average food
intake (Y1/ mice, 154.6 ± 5.2 gm · kg1 · d1;
Y1+/+ mice, 149.9 ± 3.8 gm · kg1 · d1),
or average water consumption (Y1/
mice, 67.0 ± 5.6 ml · kg1 · d1;
Y1+/+ mice, 84.7 ± 19.1 ml · kg1 · d1)
during the alcohol consumption test. To determine whether the Y1/ mice exhibited general differences
in taste preference or consumption of solutions containing calories, we
tested male mice with sucrose (a caloric compound) and quinine
solutions, using the same protocol as above. We used these tastants
because previous research has indicated that rodents perceive the taste
of alcohol as a sweet-bitter compound (Kiefer et al., 1990). There were
no significant differences between the genotypes in consumption of
either sucrose or quinine solutions (Fig. 1d). Thus,
increased consumption of alcohol by male
Y1/ mice does not appear to be
associated with altered taste preference or caloric need.
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Figure 1.
Consumption of solutions containing ethanol or
nonalcoholic tastants by male Y1 receptor knock-out
(Y1/) and wild-type (Y1+/+)
mice maintained on an inbred C57BL/6 genetic background.
a, Consumption (grams per killigram per day) of each
ethanol solution (8 d average). b, Consumption (grams
per killigram per 2 d) of the 10% ethanol solution. Consumption
measures were collected every 2 d. c,
Ethanol-preference ratios (volume of ethanol consumed/total volume of
fluid consumed) as a measure of relative ethanol preference during
consumption of the 10% ethanol solution. d, Consumption
(milliliters per killigram per day) of solutions containing sucrose
(Suc) or quinine (Qui). Mice had 2 d
of access to each taste solution. All values are means ± SEM.
ANOVAs indicated that male Y1/ mice drank
significantly more ethanol than male Y1+/+ mice.
*p < 0.05.
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Female Y1/ and
Y1+/+ mice were also tested for
consumption of ethanol solutions. Female
Y1/ mice consumed significantly more
of the 10% ethanol solution (Fig.
2a-c), but unlike male
Y1/ mice, they did not show
significant altered consumption of the 3 and 6% ethanol solutions,
suggesting a possible interaction between gender and expression of
phenotypes associated with the gene mutation. However, similar to the
male mice, increased consumption of the 10% ethanol solution by female
Y1/ mice was impressive given the
already high level of ethanol consumption by wild-type mice. During
ethanol consumption testing, the female Y1/ and
Y1+/+ mice did not differ in measures of
average body weight (Y1/ mice,
22.4 ± 1.0 gm; Y1+/+ mice, 22.7 ± 0.5 gm) or average water consumption
(Y1/ mice, 82.8 ± 13.6 ml · kg1 · d1;
Y1+/+ mice, 102.7 ± 12.4 ml · kg1 · d1).
Furthermore, female Y1/ mice did not
show altered consumption of solutions containing either sucrose or
quinine (Fig. 2d).
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Figure 2.
Consumption of solutions containing ethanol or
nonalcoholic tastants by female Y1/ and
Y1+/+ mice maintained on an inbred C57BL/6 genetic
background. a, Consumption (grams per killigram per day)
of each ethanol solution (8 d average). b, Consumption
(grams per killigram per 2 d) of the 10% ethanol solution.
Consumption measures were collected every 2 d. c,
Ethanol-preference ratios (volume of ethanol consumed/total volume of
fluid consumed) as a measure of relative ethanol preference during
consumption of the 10% ethanol solution. d, Consumption
(milliliters per killigram per day) of solutions containing sucrose
(Suc) or quinine (Qui). Mice had 2 d
of access to each taste solution. All values are means ± SEM.
ANOVAs indicated that female Y1/ mice drank
significantly more 10% ethanol solution than female
Y1+/+ mice, but there were no significant genotype
differences during assessment of the 3 and 6% ethanol solutions.
*p < 0.05.
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Ethanol-induced sedation test and plasma ethanol levels
NPY/ mice showed reduced
sensitivity to ethanol-induced sedation (Thiele et al., 1998).
Therefore, we sought to determine whether Y1/ mice were resistant to the
sedative effects of ethanol. We used male mice because they showed
increased consumption of each ethanol solution tested. Male
Y1/ mice were resistant to the
sedative effects of ethanol, regaining their righting reflex sooner
than Y1+/+ mice after injection of both
the 3.5 and 4.0 gm/kg ethanol doses (Fig.
3a). Furthermore, differences
in sensitivity to the sedative effects of ethanol (and ethanol
consumption) do not appear to be secondary to differences in acute
clearance of ethanol, because plasma ethanol concentrations at 1 and 3 hr after ethanol administration did not differ between the genotypes
(Fig. 3b).
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Figure 3.
Tests of ethanol-induced intoxication and
assessment of plasma ethanol levels with male
Y1/ and Y1+/+ mice.
a, The time that elapsed between intraperitoneal
injection of ethanol [3.5 or 4.0 gm/kg; 20% (w/v) mixed in isotonic
saline] and when the mouse could right itself onto all four paws three
times within a 30 sec interval was used as the index of latency to
right (in minutes). b, Plasma ethanol levels (in
milliliters per deciliter) 1 or 3 hr after intraperitoneal injection of
ethanol [3.5 gm/kg; 20% (w/v) mixed in isotonic saline].
c, Latency to fall (in seconds) from the rotarod on the
last trial of each test day. Mice were first habituated
(H) to walking on the rotarod apparatus
for 3 d. For the next 2 d, mice were given an intraperitoneal
injection of saline (S1 and S2) before
placement on the rotarod, and on the final day of the study
(E), mice were given an intraperitoneal injection
of ethanol [2.5 gm/kg; 20% (w/v) mixed in isotonic saline]
immediately before rotarod testing. All values are means ± SEM.
ANOVAs indicated that Y1/ mice recovered from
ethanol-induced sedation significantly sooner than
Y1+/+ mice. *p < 0.05.
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Accelerating rotarod test
It has been suggested previously that multiple assessment tools
should be used when studying knock-out mice to avoid misinterpretation of gene function (Boehm et al., 2000). Therefore, we determined whether
male Y1/ mice also showed reduced
sensitivity to ethanol-induced motor impairment with the accelerating
rotarod test, a common measure of drug-induced ataxia. Relative to
wild-type mice, Y1/ mice did not
differ in latency to fall from an accelerating rotarod immediately
after injection of a 2.5 gm/kg dose of ethanol (Fig. 3c).
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DISCUSSION |
Here we provide evidence suggesting that the NPY Y1 receptor
regulates voluntary alcohol consumption and some of the acute intoxicating effects caused by administration of this drug. The high
level of alcohol consumption by Y1/
mice does not appear to be related to the taste and/or caloric properties of ethanol, because the Y1/
mice showed normal consumption of solutions containing either sucrose
or quinine and normal food intake. Furthermore, resistance to
ethanol-induced sedation (and high ethanol consumption) are not likely
related to high ethanol metabolism, because the
Y1/ mice showed normal plasma ethanol
levels. Interestingly, Y1/ mice showed
normal ethanol-induced ataxia on the rotarod test, suggesting that
resistance to the neurobiological effects of ethanol in the
Y1/ mice may be task-dependent, an
observation that has been made with another mutant mouse model (Boehm
et al., 2000). Alternatively, it is possible that the 2.5 gm/kg ethanol
dose used for the rotarod test may have been too high, thus producing a
ceiling effect that prevented the detection of significant differences
between the genotypes.
In the brain, NPY acts through Y1, Y2, and Y5 receptors, all of which
couple to heterotrimeric G-proteins that inhibit production of cAMP
(Heilig and Widerlov, 1995; Gerald et al., 1996). The Y1 and Y5
receptors have been identified as postsynaptic (Michel, 1991; Naveilhan
et al., 1998), whereas the Y2 receptor appears to be a presynaptic
autoreceptor that inhibits synaptic release of NPY (Chen et al., 1997).
The present results with Y1/ mice are
consistent with those obtained with
NPY/ mice (Thiele et al., 1998) and
suggest that the actions of NPY on voluntary ethanol consumption and
ethanol-induced sedation are modulated by postsynaptic Y1 receptor
signaling. Given the postsynaptic location of the Y5 receptor, one
might also predict that Y5 receptor knock-out
(Y5/) mice would show increased
ethanol consumption. However, we have found previously that
Y5/ mice showed normal consumption of
solutions containing ethanol (Thiele et al., 2000a). Together, the data
suggest that ethanol consumption is modulated by the Y1 receptor,
whereas other NPY receptors may not be involved.
Because ethanol has calories, it is possible that the Y1 receptor
modulates alcohol intake via the same hypothalamic system thought to
stimulate feeding behavior (Palmiter et al., 1998). However, this does
not seem likely, because Y1/ mice
drank more ethanol solution yet had normal to reduced daily food intake
(Pedrazzini et al., 1998) and did not show altered consumption of the
caloric sucrose solution in the present study. Alternatively, there is
increasing evidence from both human and animal research indicating that
resistance to the intoxicating effects of ethanol is often associated
with high levels of ethanol drinking (Schuckit, 1986, 1988, 1994;
Thiele et al., 1998, 2000b; Hodge et al., 1999). One possible
physiological role for the Y1 receptor may be to promote some of the
intoxicating effects of ethanol, perhaps as a mechanism to limit
alcohol intake. As such, a lack of Y1 receptor signaling would cause a
resistance to the intoxicating effects of ethanol, thus eliminating
this protective system and increasing the risk for high alcohol intake.
Consistent with this hypothesis is evidence showing that central
infusion of NPY potentiated ethanol-induced sleep time in rats
(Badia-Elder et al., 2001b) and evidence that Y1 receptor signaling
modulates the sedative effects of sodium pentobarbital (Naveilhan et
al., 2001).
The Y1 receptor may modulate ethanol consumption by inhibiting cAMP
production (Heilig and Widerlov, 1995; Gerald et al., 1996). In fact,
recent data provide direct evidence that cAMP and cAMP-dependent
protein kinase A (PKA) signaling regulate neurobiological responses to
ethanol. Mutant mice lacking the RII subunit of PKA drank more
ethanol and were resistant to ethanol-induced sedation despite normal
plasma ethanol levels (Thiele et al., 2000b). A similar pattern of
results was found in mice with targeted disruption of the stimulatory
G-protein Gs , whereas transgenic mice overexpressing Gs in
forebrain showed reduced ethanol sensitivity (Wand et al., 2001).
Finally, inactivation of the Drosophila amnesiac gene, which
encodes a secreted neuropeptide that stimulates cAMP production, rendered flies more sensitive to ethanol-induced sedation (Moore et
al., 1998). It will be important to determine whether
Y1/ mice have altered levels of cAMP
and/or PKA, and whether cAMP antagonists can "normalize" ethanol
drinking in these mice.
Several examples in the literature indicate that ethanol consumption
and resistance are inversely related to NPY signaling. Both the
NPY/ and
Y1/ mice showed increased ethanol
consumption and reduced sensitivity to ethanol-induced sedation,
whereas NPY-overexpressing mice showed low ethanol consumption and
increased ethanol-induced sleep time (Thiele et al., 1998).
Furthermore, both the Indiana alcohol-preferring and high
alcohol drinking rats, which were selectively bred for high
ethanol consumption, showed reduced NPY levels in the central nucleus
of the amygdala (Ehlers et al., 1998; Hwang et al., 1999), and central
infusion of NPY was found to attenuate the high ethanol consumption but
increase ethanol-induced sleep time in alcohol preferring rats
(Badia-Elder et al., 2001a,b). However, it has also been reported that
central infusion of NPY either has no effect on ethanol drinking
(Slawecki et al., 2000) or can increase ethanol consumption when
infused directly into the paraventricular nucleus of the hypothalamus
(Kelley et al., 2001). The latter example suggests that NPY may have
brain region-specific effects on voluntary ethanol consumption.
It is noteworthy that the Y1 receptor has been shown to mediate the
anti-anxiety actions of NPY (Heilig et al., 1993). Furthermore, both
the P rats and the NPY/ mice show high
basal levels of anxiety-associated behaviors (Stewart et al., 1993;
Thiele et al., 1998). Thus, high ethanol consumption may be secondary
to high levels of anxiety. It will be important to determine whether
Y1/ mice show altered basal levels of
anxiety, and whether there is a direct link between anxiety and alcohol
consumption in these knock-out and selectively bred models.
In summary, we show here that the NPY Y1 receptor is important for
regulating ethanol intake and sensitivity to the sedative effects of
ethanol. Given the health and social problems related to alcohol
dependence, central NPY Y1-mediated pathways that regulate ethanol
consumption might represent attractive therapeutic targets for the
treatment of alcohol use disorders.
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FOOTNOTES |
Received Oct. 15, 2001; revised Nov. 26, 2001; accepted Nov. 27, 2001.
This work was supported by National Institutes of Health Grants AA00258
and AA13573 (T.E.T), by the University of Washington Alcohol and Drug
Abuse Institute, and by a generous donation from the Brunstad family to
T. E. T. We thank G. I. Miura for help with genotyping
mice and D. J. Marsh, R. D. Palmiter, and I. L. Bernstein for helpful discussions.
Correspondence should be addressed to Dr. Todd E. Thiele, Department of
Psychology, University of North Carolina, Davie Hall, CB# 3270, Chapel
Hill, NC 27599-3270. E-mail: thiele{at}unc.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, 2002, 22:RC208 (1-6). The
publication date is the date of posting online at
www.jneurosci.org.
| |
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