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The Journal of Neuroscience, July 15, 2001, 21(14):5297-5303
The cAMP-Protein Kinase A Signal Transduction Pathway
Modulates Ethanol Consumption and Sedative Effects of Ethanol
Gary
Wand1, 2,
Michael
Levine1, 3,
Larry
Zweifel1,
William
Schwindinger5, and
Ted
Abel4
Departments of 1 Medicine, 2 Psychiatry,
and 3 Pediatrics, The Johns Hopkins University School of
Medicine, Baltimore, Maryland 21205, 4 Department of
Biology, University of Pennsylvania, Philadelphia, Pennsylvania
19104, and 5 Weis Center for Research, The Geisinger
Clinic, Danbury, Pennsylvania 17822
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ABSTRACT |
Ethanol and other drugs of abuse modulate cAMP-PKA signaling
within the mesolimbic reward pathway. To understand the role of the
cAMP-PKA signal transduction in mediating the effects of ethanol, we
have studied ethanol consumption and the sedative effects of ethanol in
three lines of genetically modified mice. We report that mice with the
targeted disruption of one Gs allele as well as mice with reduced
neuronal PKA activity have decreased alcohol consumption compared with
their wild-type littermates. Genetic reduction of cAMP-PKA signaling
also makes mice more sensitive to the sedative effects of ethanol,
although plasma ethanol concentrations are unaffected. In contrast,
mice with increased adenylyl cyclase activity resulting from the
transgenic expression of a constitutively active form of Gs in
neurons within the forebrain are less sensitive to the sedative effects
of ethanol. Thus, the cAMP-PKA signal transduction pathway is critical
in modulating sensitivity to the sedative effects of ethanol as well as
influencing alcohol consumption.
Key words:
alcohol; sedation; adenylyl cyclase; protein kinase A; cAMP; alcoholism
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INTRODUCTION |
The cAMP-PKA signal transduction
pathway is a ubiquitous cascade that modulates numerous cellular events
within neurons (Abel and Kandel, 1998 ; Self et al., 1998). The
stimulatory G-protein Gs couples and amplifies ligand-induced signals
transmitted from receptors to multiple isoforms of adenylyl cyclase. We
have previously shown that alcohol-preferring rats have increased
adenylyl cyclase activity and increased expression of the subunit
of Gs (Gs) in mesolimbic regions of the brain (e.g., nucleus
accumbens and ventral tegmental area) compared with
alcohol-nonpreferring rats (Froehlich and Wand, 1997). Levels of Gs
are similarly increased in blood cell membranes from humans at
increased risk for alcoholism (Wand et al., 1994). In addition, a
series of studies have identified biochemical abnormalities in this
pathway in erythrocyte, lymphocyte, and platelet membranes derived from
alcoholic persons (Tabakoff et al., 1988; Gordon et al., 1991; Waltman
et al., 1993; Parsian et al., 1996; Menninger et al., 1998). Ethanol
and other drugs of abuse modulate cAMP-PKA signaling within the
mesolimbic reward pathway (Hoffman and Tabakoff, 1990; Self et al.,
1998; Spanagel and Weiss, 1999). Because the magnitude of adenylyl
cyclase activity as well as vulnerability to alcoholism are both
influenced by strong genetic determinants (Devor et al., 1991; Foroud
and Li, 1999), it is conceivable that genes controlling cAMP-PKA
signaling in the mesolimbic reward pathway play an important role in
determining genetic vulnerability for alcoholism.
Compared with the offspring of nonalcohol-dependent parents, the
offspring of alcoholics have a 4- to 10-fold increased probability of
developing alcoholism during their teenage years and adulthood (Schuckit, 1994, 2000). Human studies of "at risk" individuals have
established a premorbid phenotype characterized by increased drug
liking and decreased sensitivity to sedative effects of alcohol (Schuckit, 2000). Therefore, we hypothesized that genetically altering
the neuronal cAMP-PKA signaling pathway would modulate alcohol
drinking behavior as well as sensitivity to the sedative effects of alcohol.
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MATERIALS AND METHODS |
Animals. The Gnas ( /+) mutation was generated by
homologous recombination in J1 embryonic stem (ES) cells
(Schwindinger et al., 1997). One targeted ES cell clone that was
introduced into C57BL/6J embryos resulted in viable, fertile, male
chimeras that transmitted the targeted Gnas allele to their progeny.
The Gnas (/+) was maintained on three backgrounds: C57BL/6J, 129SvEv, and 129SvEv xCD1. The Gnas (/+) mutation carried in C57BL/6
background was generated by breeding chimeras to C57BL/6J, which were
then back-crossed with C57BL/6J mice (Taconic, Germantown, NY).
Similarly, Gnas (/+) carried in 129SvEv background were generated by
breeding chimeras to 129SvEvs (Taconic), which were then back-crossed
with 129SvEV mice. Gnas (/+) carried in 129SvEv × CD1
background was generated by breeding Gnas (/+) carried in 129SvEv
background with CD1s (The Jackson Laboratory, Bar Harbor, ME)
and then inbreeding for subsequent generations. Gnas (/+) mice were
at N3-N7 for this study and genotyped as described (Schwindinger et
al., 1997). Because of genetic imprinting of the Gnas gene (Hayward et
al., 1998), only mice with maternal inheritance of the disrupted allele were used in these studies. The R(AB) and GsQ227L transgenes are
maintained in a hemizygous state on a C57BL/6J background (N7-N9) and
genotyped as described (Abel et al., 1997, 1998).
All mice lines develop normally and are fertile. Colonies and
experimental rooms were maintained at 22°C with a 12 hr light/dark cycle, and testing occurred during hours 2-6 of the light phase. Both
males and females were used for the studies, and no gender differences
were noted. Mice were between the ages of 2 and 4 months at the time of
testing. Animal care and handling procedures were in accordance with
institutional and National Institutes of Health guidelines.
Preference test. Mice were housed individually and
habituated to their home cage for 1 week. During this period mice were allowed equal access to two, 50 ml feeding tubes (Bio-Serv) containing water. Mice were then offered 3% ethanol (v/v) versus water for 3 d. Tube positions were changed every day to control for position preferences. Immediately after exposure to 3% ethanol, choice between
6% ethanol and water was offered for 3 d, 10% versus water for
3 d, and finally 20% ethanol versus water for 3 d. Body
weight and food consumption were averaged over each 3 d trial.
Ethanol consumption was measured as total volume consumed per trial or grams of ethanol per kilogram to correct for differences in body weight. Ethanol preference is defined as volume of ethanol consumed divided by total volume consumed (ethanol + water). After a 1 week
hiatus, sucrose and quinine preferences were obtained in a similar
manner on the same mice with the substitution of ethanol with either
1.7 and 4.5% sucrose or 0.015 and 0.03 mM
quinine hemisulfate. Two-way, 2 × 2 (genotype × concentration) repeated-measure ANOVAs were used for statistical
analysis for all preference studies.
Test of sensitivity for ethanol-induced sedation. Mice were
given an intraperitoneal injection of 3.5 gm/kg ethanol (20% v/v in
0.9% saline) and then placed on their backs in a V-shaped trough (13 × 10 cm). Loss of righting reflex is defined as the time
interval between injection and loss of ability to stand on three of
four paws. Gain of righting reflex is defined as the time interval between loss of righting reflex and regaining of righting reflex. Ethanol-induced sedation is expressed as sleep time (time to gain righting reflex minus time to loss of righting reflex). Data were analyzed by t test.
Plasma ethanol concentration. We took ~20 µl of tail
blood samples at the indicated time points after injection. Samples
were microcentrifuged 20 min (14,000 rpm) at 4°C and analyzed
immediately. Plasma ethanol was determined by an ADH/NADH assay
(Sigma Diagnostic) following manufacturer specifications. Two-way,
2 × 2 (genotype × time) repeated-measure ANOVAs were used
for statistical analysis.
Adenylyl cyclase activity and immunoblots. Membranes were
prepared, and adenylyl cyclase assays and immunoblots were performed as
described (Froehlich and Wand, 1997). G-protein signals were densitized
using a Personal Densitometer (Molecular Dynamics, Sunnyvale, CA), and
Gs expression was normalized to levels of Go, which did not
differ by genotype. Densitometric data were analyzed by t test.
In situ hybridization. Mouse brains were dissected and
rapidly frozen in Tissue-Tek embedding medium. Coronal sections (20 µM) were fixed and hybridized to a
transgene-specific [-35S]dATP-labeled
oligonucleotide probe as described (Abel et al., 1997). Slides were
exposed for 4 weeks to Kodak (Eastman Kodak, Rochester, NY) Biomax
MR autoradiographic film.
[3H]Ro15-1788 binding to brain
membranes were performed as previously described (Hodge et al.,
1999).
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RESULTS |
To begin studying the functional relationship between Gs and
ethanol consumption and sensitivity, we examined mice with heterozygous inactivation of the Gnas gene encoding Gs [Gnas (/+) mice] that was generated by disruption of exon 1 (Schwindinger et al.,
1997). Quantitative immunoblot studies showed that levels of
Gs in Gnas (/+) mice were significantly reduced relative to
wild-type (WT) levels in multiple brain regions, including the nucleus
accumbens (Fig. 1a),
hypothalamus (100 ± 18 vs 61 ± 5; p < 0.02), hippocampus (100 ± 16 vs 53 ± 7; p < 0.01), and cerebellum (100 ± 14 vs 62 ± 11;
p < 0.05). Nissl-stained as well as hematoxylin- and
eosin-stained sagittal sections of brains from Gnas (/+) mice showed
no gross anatomical abnormalities within the hypothalamus or other
regions (data not shown). Figure 1b shows that adenylyl
cyclase activity in nucleus accumbens membranes from Gnas (/+) mice
is significantly reduced relative to WT membranes when stimulated with
fluoroaluminate (AlF) and guanosine triphosphate (GTP). Table
1 shows reduced AlF-stimulated adenylyl
cyclase activity observed in membranes prepared from Gnas (/+)
hypothalamus (30% reduction), cerebellum (23% reduction), hippocampus
(35% reduction), frontal cortex (22% reduction), and brainstem (21%
reduction).
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Figure 1.
Comparison of nucleus accumbens Gs protein
levels and adenylyl cyclase activity in Gnas (/+) and wild-type
littermates in C57BL/6J background. Antisera to Gs recognizes 52 and
45 kDa forms of the protein (top panel). The 52 and 45 kDa signals were summed for densitometric analysis
(middle panel). The filter was stripped and
reprobed with Go antisera for normalization of Gs levels. Go
levels did not differ by genotype. Each lane represents
membranes from one mouse (40 µg/lane). AlF- and GTP-stimulated
adenylyl cyclase activity in nucleus accumbens membranes
(*p < 0.05) (bottom
panel).
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We next determined whether the sedative effects of ethanol are altered
in Gnas (/+) mice because of the potential role of cAMP-PKA
signaling in this effect (Froehlich and Wand, 1997). Gnas (/+)
mice were more sensitive to the sedative effects of ethanol, taking
twice as long to regain their righting reflex as WT littermates (Fig.
2a). Differences in
sensitivity were not caused by differences in acute clearance of
ethanol, because plasma ethanol concentrations did not differ between
genotypes (Fig. 2b).
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Figure 2.
Sleep time as a measurement of sensitivity to the
sedative hypnotic effects of ethanol (3.5 g/kg). a, Gnas
(/+) versus wild-type, *p < 0.001. c, R(AB) versus wild-type, *p < 0.001. e, Q227L versus wild-type, *p < 0.001. b, d, f, Blood
ethanol concentrations at the indicated time points
(n = 6-12 per genotype). Values are mean ± SEM.
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To test ethanol consumption, mice were given 24 hr access to two
feeding tubes, one containing water, and the other 3% ethanol. The
concentration of ethanol was then increased to 6, 10, and 20% ethanol
every 3 d for further trials. Gnas (/+) mice consumed only
40-50% as much ethanol as WT mice (Fig.
3a-c). When consumption of
ethanol is expressed relative to total fluid consumption
(ethanol-preference ratio), Gnas (/+) mice showed a lower intake of
ethanol and preferred water to ethanol (preference ratio, <0.5) during
access to 6, 10, and 20% ethanol solutions. By contrast, WT mice
consistently preferred ethanol to water across all ethanol
concentrations <20%. There were no significant differences between
genotypes in measures of average total fluid consumption (water plus
ethanol, in milliliters) (Fig. 3d).
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Figure 3.
Consumption of ethanol by Gnas (/+) mice and
wild-type littermates in C57BL/6J background. a,
Consumption (in grams per kilogram) of 6% ethanol solution
(genotype, F(1,14) = 7.28, p = 0.019). b, Consumption
(in grams per kilogram per day) of each ethanol solution, 3 d
average, (genotype, F(1,14) = 19.37, p = 0.001). c, Ethanol-preference
ratios (volume of ethanol consumed per total volume of fluid consumed)
as a measure of relative ethanol preference (genotype,
F(1,14) = 27.48, p = 0.0001). d, Total fluid consumption (ethanol plus
water, in milliliters). e, f, Preference ratios for
sucrose and quinine (volume of solution consumed per total volume of
fluid consumed). g, h, Average total food
intake per day over trial period and average body weight at the start
of trials. Values are mean ± SEM (n = 6 per
genotype and concentration). Groups were compared by two-way repeated
measures ANOVAs. *p < 0.05 relative to wild-type
littermates, post hoc Tukey.
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To determine whether these differences might reflect a more global
change in taste preferences, we tested Gnas (-/+) and WT mice with
sucrose and quinine solutions, using the same protocol as above. There
were no significant differences between genotypes in preference for the
sweet and bitter compounds, relative to water (Fig.
3e,f). Decreased preference for ethanol by mice with reduced Gs expression did not generalize to other flavored
solutions. Furthermore, there were no significant differences between
genotypes in measures of average food intake (Fig.
4g) or body weight (Fig. 3h). Thus, the targeted disruption of one Gnas allele with
resultant decreases in Gs protein expression and adenylyl cyclase
activity converted ethanol-preferring mice into ethanol nonpreferring
mice.
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Figure 4.
Consumption of ethanol by R(AB) mice and wild-type
littermates in C57BL/6J background. a, Consumption (in
grams per kilogram) of 6% ethanol solution (genotype,
F(1,12) = 6.0, p = 0.034). b, Consumption (in grams per kilogram per day)
of each ethanol solution, 3 d average (genotype,
F(1,12) = 12.17, p = 0.006). c, Ethanol-preference ratios (volume of
ethanol consumed per total volume of fluid consumed) as a measure of
relative ethanol preference (genotype,
F(1,12) = 20.55, p = 0.001). d, Total fluid consumption (ethanol plus
water, in milliliters). e, f, Preference ratios for
sucrose and quinine (volume of solution consumed per total volume of
fluid consumed). g, h, Average total food
intake per day over trial period and average body weight at the start
of trials. Values are mean ± SEM (n = 6 per
genotype and concentration). Groups were compared by two-way repeated
measures ANOVAs. *p < 0.05 relative to wild-type
littermates, post hoc Tukey test.
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To be more certain that inactivation of one Gnas allele was responsible
for decreased preference for ethanol and increased sensitivity to the
sedative effect of ethanol, we studied the effects of Gnas (/+)
carried in two other genetic backgrounds: 129/SvEv and CD1X129/SvEv.
Regardless of genetic background, Gnas (/+) mice have increased
sensitivity to the sedative effects of ethanol (Table
2) and decreased alcohol preference
(Table 3) compared with their WT
littermates.
Gs modulates all known isoforms of adenylyl cyclase as well as
L-type calcium channels (Blumenstein et al., 1999). To determine if the
cAMP-PKA signaling pathway distal to cAMP generation plays a role in
ethanol consumption and ethanol-induced sedation, we studied transgenic
mice that express R(AB), a dominant inhibitor isoform of the regulatory
subunit of PKA in neurons of the forebrain under the control of
CaMKII gene promoter (Abel et al., 1997). These mice have reduced
PKA activity limited to the hippocampus and forebrain regions but
normal activity within the cerebellum, brainstem, hypothalamus, and
other brain regions (Abel et al., 1997). Similar to Gnas (+/), R(AB)
mice were more sensitive to ethanol-induced sedation than WT
littermates (Fig. 2c,d). Increased sensitivity to sedation
in R(AB) mice was not accompanied by increased numbers of
GABAA receptors or receptor affinity (data not
shown). Moreover, R(AB) mice drank significantly less ethanol at all
the concentrations tested (Fig. 4a-c) and had a lower
preference for ethanol compared with WT littermates. Because of the
restricted expression pattern of the R(AB) transgene, the data argue
PKA acts within the hippocampus, cortex, striatum, or nucleus accumbens to modulate these effects of ethanol.
To further elucidate the relationship between Gs expression and
ethanol, we examined transgenic mice that express a constitutively active form of Gs (Gs Q227L) in neurons limited to the
hippocampus, neocortex, striatum, and amygdala under the control of the
CaMKII promoter (Fig. 5). This mutant
form of Gs is constitutively active because of its reduced GTPase
activity resulting in increased adenylyl cyclase activity (Landis et
al., 1989). We found twofold to threefold increases in basal adenylyl
cyclase activity in membranes derived from hippocampus, nucleus
accumbens, and frontal cortex of transgenic mice compared with wild
type (Table 4). No genotype differences
were observed in membranes derived from cerebellum, a region where the
transgene is not expressed.
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Figure 5.
Regional distribution of GsQ227L transgene. To
determine the distribution of transgene expression in the brain, we
performed in situ hybridization studies using a
transgene-specific oligonucleotide as described (Abel et al., 1997b).
In coronal sections taken from a GsQ227L transgenic mouse,
expression of the transgene can be observed in the cortex and striatum
(rostral section, left) and in the hippocampus (caudal
section, right). No transgene expression is observed in
the cerebellum, hypothalamus, thalamus, or brainstem. No expression is
seen in wild-type control animals (data not shown).
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In contrast to Gnas (/+) and R(AB) mice, GsQ227L transgenic mice,
which exhibit increased adenylyl cyclase activity, were markedly less
sensitive to ethanol-induced sedation compared with WT littermates
(Fig. 2e,f). However, transgenic mice had similar ethanol consumption and preference scores compared with WT mice (Fig.
6).
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Figure 6.
Consumption of ethanol by GsQ227L transgenic
mice and wild-type littermates in C57BL/6J background.
a, Consumption (in grams per kilogram per day) of each
ethanol solution, 3 d average. b,
Ethanol-preference ratios [volume of ethanol consumed (in milliliters)
per total volume of fluid consumed (in milliliters)]) as a measure of
relative ethanol preference.
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DISCUSSION |
Our studies show that reduced signaling through the cAMP-PKA
system in the brain, whether because of decreased expression of Gs
or inhibition of PKA, changed an ethanol-preferring line of mice
(C57BL/6J) into ethanol nonpreferring rodents. In Gnas (/+) mice,
this phenotype was maintained when the genetic background was varied.
Thus, the cAMP-PKA signal transduction pathway is critical in
modulating ethanol intake. However, it is important to note that
upregulation of cAMP-PKA signaling, through use of the GsQ227L
transgene, did not increase ethanol consumption. The inability to find
a difference in alcohol preference in GsQ227L transgenic mice and WT
may reflect that C57BL/J6 mice are an alcohol-preferring line and
already exhibit exceedingly high alcohol preference. We speculate there
is a ceiling effect. Placement of the transgene in a mouse line that is
not alcohol-preferring will determine if transgene expression can
create an alcohol-preferring mouse. However, there may be a more
complex relationship between the sedative and rewarding effects of
alcohol than previously suspected.
Our data provides the first demonstration that the upregulation and
downregulation of the cAMP-PKA signaling produces opposite phenotypes
vis-à-vis sedative effects of alcohol in mammals. Furthermore,
expression of the R(AB) and GsQ227L transgene is limited to the
forebrain, striatum, and hippocampus. The transgenes are not expressed
in the cerebellum or hypothalamus (or any other brain regions), which
have always been proposed sites for ethanol-induced sedation. Thus, our
data are the first to rule out specific brain regions as being
important for both alcohol-induced sedation and alcohol preference
mediated by cAMP-PKA signaling. Moreover, the CaMKII promoter is
not expressed prenatally, indicating that our observations are not the
product of developmental alterations induced by prenatal transgene expression.
The role of cAMP-PKA system in mediating sedative or hypnotic effects
of ethanol extends to invertebrates as well. In Drosophila inactivation of the amnesiac gene, which encodes a secreted
neuropeptide that induces cAMP production, as well as mutations in
rutabaga, a calcium-sensitive isoform of adenylyl cyclase,
makes flies more sensitive to ethanol-induced sedation (Moore et al.,
1998). Findings from R(AB) mice support the notion that events distal
to cAMP are important in mediating the observed differences in
sensitivity to ethanol.
One mechanism by which the absence or reduction in PKA could enhance
ethanol-induced sedation is by increasing the number of
GABAA receptors. However, we did not find
increased GABAA receptor number or affinity in R(AB) mice.
Alternatively, it is known that GABA-induced chloride currents are
dampened by PKA-induced phosphorylation of specific GABA receptor
subunits (Leidenheimer et al., 1991; Whiting et al., 1999). Therefore,
it is possible that Gnas (/+) and R(AB) mice with low adenylyl
cyclase and PKA activity may be more sensitive to the sedative effects
of alcohol because of reduced phosphorylation of GABA receptors,
resulting in a greater chloride flux compared with wild-type mice. In
contrast, GsQ227L mice with constitutively active Gs may be less
sensitive to the hypnotic effects of alcohol because of enhanced
PKA-induced phosphorylation GABA receptors, resulting in a dampening of
chloride currents. Overall, our observations fit well with the widely
held assumption that persons at increased risk for alcoholism are less
sensitive to the sedative and hypnotic properties of ethanol (Schuckit, 2000).
In summary, our results show that cAMP-PKA signal transduction
modulates ethanol intake and sensitivity to sedative effects of
ethanol, and they may help explain the observations from several other
studies. For example, both the 5-HT1B receptor
(Zgombick and Branchek, 1998) and neuropeptide Y (Thiele et al.,
1998) inhibit adenylyl cyclase activity.
5-HT1B receptor-deficient as well as neuropeptide
Y-deficient mice have increased alcohol consumption and reduced
sensitivity to alcohol (Crabbe et al., 1996; Navarro et al., 2000). In
contrast, neuropeptide Y overexpressing mice have the opposite
phenotype (Thiele et al., 1998). Moreover,
RII knock-out mice, which are
speculated to have chronically unregulated catalytic units of PKA, also
have increased alcohol intake and reduced sensitivity to alcohol
(Thiele et al., 2000). Alcoholism is a polygenic disorder with genetic
and environmental determinants. We speculate that persons at increased
risk for alcoholism may carry one or more functional polymorphisms
affecting the neurotransmitters, receptors, and other proteins
responsible for maintaining integrity of the cAMP-PKA signaling within
the forebrain and mesolimbic system.
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FOOTNOTES |
Received March 13, 2001; revised April 18, 2001; accepted April 19, 2001.
This work was supported by National Institutes of Health (NIH) Grant
AA09000 and the Lattman Foundation (G.W.); by NIH Grants AG18199 and
MH60244, the Whitehall Foundation, the University of Pennsylvania
Research Foundation, and a Young Investigator Award from the Mental
Retardation and Developmental Disabilities Research Center at
Children's Hospital of Philadelphia (HD26979) (T.A.); and by NIH Grant
DK18213 (M.L). T.A. is also a John Merck Scholar. We thank Haejin Kim
for her technical support, Arati Sadalge for her assistance with the
in situ hybridization experiment, Alan Young for his
help with dissections for the adenylyl cyclase assays in GsQ227L
mice, and Dr. Xiaoju Yang for running adenylyl cyclase assays in this
mouse line.
Correspondence should be addressed to Dr. Gary Wand, Professor of
Medicine and Psychiatry, The Johns Hopkins University School of
Medicine, Ross Research Building, Room 863, 720 Rutland Avenue, Baltimore, MD 21205. E-mail: gwand{at}welch.jhu.edu.
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ABSTRACT
INTRODUCTION
