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 Previous Article
The Journal of Neuroscience, October 1, 2002, 22(19):8771-8777
Mutation of the  2A-Adrenoceptor Impairs Working
Memory Performance and Annuls Cognitive Enhancement by Guanfacine
Jenna S.
Franowicz1,
Lynn E.
Kessler1,
Catherine
M. Dailey
Borja1,
Brian K.
Kobilka2,
Lee E.
Limbird3, and
Amy F. T.
Arnsten1
1 Department of Neurobiology, Yale University School of
Medicine, New Haven, Connecticut 06510, 2 Howard Hughes
Medical Institute and Departments of Medicine and Molecular and
Cellular Physiology, Stanford University, Palo Alto, California
94305, and 3 Department of Pharmacology, Vanderbilt
University School of Medicine, Nashville, Tennessee 37232
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ABSTRACT |
Norepinephrine strengthens the working memory, behavioral
inhibition, and attentional functions of the prefrontal cortex through actions at postsynaptic  2-adrenoceptors
(2-AR). The 2-AR agonist guanfacine
enhances prefrontal cortical functions in rats, monkeys, and human
beings and ameliorates prefrontal cortical deficits in patients with
attention deficit hyperactivity disorder. The present study examined
the subtype of 2-AR underlying these beneficial effects.
Because there are no selective 2A-AR,
2B-AR, or 2C-AR agonists or antagonists,
genetically altered mice were used to identify the molecular target of
the action of guanfacine. Mice with a point mutation of the
2A-AR, which serves as a functional knock-out, were
compared with wild-type animals and with previously published studies
of 2C-AR knock-out mice (Tanila et al., 1999 ). Mice were
adapted to handling on a T maze and trained on either a spatial delayed
alternation task that is sensitive to prefrontal cortical damage or a
spatial discrimination control task with similar motor and motivational
demands but no dependence on prefrontal cortex. The effects of
guanfacine on performance of the delayed alternation task were assessed
in additional groups of wild-type versus 2A-AR mutant
mice. We observed that functional loss of the 2A-AR
subtype, unlike knock-out of the 2C-AR subtype, weakened performance of the prefrontal cortical task without affecting learning
and resulted in loss of the beneficial response to guanfacine. These
data demonstrate the importance of 2A-AR subtype
stimulation for the cognitive functions of the prefrontal cortex and
identify the molecular substrate for guanfacine and novel therapeutic interventions.
Key words:
prefrontal cortex; norepinephrine; mice; attention
deficit hyperactivity disorder; adrenoceptor subtype; delayed
alternation; neuropsychiatric disorder
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INTRODUCTION |
The prefrontal cortex (PFC)
regulates behavior using working memory, guiding both overt behaviors
and the contents of attentional focus, inhibiting inappropriate
responses and organizing plans for the future (Goldman-Rakic, 1996;
Robbins, 1996). Deficits in PFC function are common in many
neuropsychiatric disorders (Weinberger et al., 1986; Barkley et al.,
1992; Blumberg et al., 1999) and are a fundamental feature of ailments
such as attention deficit hyperactivity disorder (ADHD), in which
symptoms of impulsivity correlate with reduced size of the right PFC
(Casey et al., 1997).
Recent studies have shown that norepinephrine (NE) has a critical
beneficial influence on PFC functions through actions at postsynaptic
2-adrenergic receptors
(2-ARs) (for review, see Avery et al., 2000).
For example, systemic administration of 2-AR agonists such as guanfacine (GFC) to rats, monkeys, or human
beings enhances performance of PFC tasks (Arnsten et al., 1988; Carlson et al., 1992; Jakala et al., 1999). Similarly, direct infusion of
2-AR agonists into the PFC improves cognitive
function, whereas infusions outside the relevant PFC region are
ineffective (Tanila et al., 1996; Mao et al., 1999). On the basis of
research in animals, guanfacine is currently in use for the treatment
of ADHD in children and adults (Scahill et al., 2001; Taylor and Russo,
2001), particularly in patients for whom stimulant medication is
contraindicated. However, the 2-AR subtype
underlying these important beneficial effects is not known.
Three 2-AR subtypes have been cloned in
humans: the 2A-AR,
2B-AR, and 2C-AR,
with the 2A-AR and
2C-AR, but not the
2B-AR, subtypes localized in the PFC (for
review, see Aoki et al., 1994; MacDonald et al., 1997). Previous
studies in monkeys used agonists with varying affinities for the
2A-AR, 2B-AR, and
2C-AR to attempt to dissect the subtype or
subtypes underlying the cognitive-enhancing, hypotensive, and sedating
actions of these agents (Arnsten et al., 1988; Arnsten and Leslie,
1991). These pharmacological analyses indicated that the
cognitive-enhancing effects were mediated by the
2A-AR, whereas the hypotensive and sedating
actions were mediated by the 2B-AR and
2C-AR. It is now known that these conclusions
were erroneous. Studies of mice with genetically altered 2-AR subtypes demonstrated conclusively that
the 2A-AR subtype mediates the hypotensive
actions of 2-AR agonists (Link et al., 1996;
MacMillan et al., 1996), and the sedative effects of these agents
involve 2A-AR actions as well (for review, see
MacDonald et al., 1997). The faulty conclusions from the previous
pharmacological studies most likely arose from several factors: (1)
there are no highly selective 2A-AR,
2B-AR, or 2C-AR
agonists or antagonists to dissociate actions between the subtypes; (2)
many 2-AR compounds have nonadrenergic actions
as well (e.g., at imidazoline I1 receptors) that
can alter blood pressure, sedation, and cognition function (e.g., the
potent hypotensive effects of clonidine most likely arise from a
combination of 2-AR and
I1 receptor actions); and (3) differences in
bioavailability can confuse measures of potency (e.g., clonidine enters
the brain more quickly than guanfacine). Thus, studies in mice with
genetically altered 2-AR subtypes are needed
to rigorously determine the 2-AR subtype
underlying the cognitive-enhancing effects of NE and
2-AR agonists for the first time. A recent
study showed that 2C-AR knock-out mice exhibit normal spatial working memory performance and normal enhancement of
performance by an 2-AR agonist (Tanila et al.,
1999). The present study performed analyses in mice with a mutation of
the 2A-AR subtype (MacMillan et al.,
1996).
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MATERIALS AND METHODS |
Design
2A-AR mutant mice were compared with
wild-type controls in their ability to habituate to handling in a T
maze and subsequently to learn and perform a task dependent on the PFC,
spatial delayed alternation in a T maze (Larsen and Divac, 1978). This
test of spatial working memory requires behavioral inhibition and
attentional regulation, particularly as delays are increased. Wild-type
and 2-AR mutant mice were also compared for
their ability to learn a control task, spatial discrimination in the T
maze, which has the same motor and motivational demands but does not
depend on the PFC (Boyd and Thomas, 1977). Finally, wild-type and
2-AR mutant mice were assessed on the delayed
alternation task for their response to guanfacine, an
2-AR agonist that in vitro prefers the 2A-AR by 10- to 60-fold (Uhlen and
Wikberg, 1991; Devedjian et al., 1994), and in vivo improves
PFC cognitive function (Arnsten et al., 1988; Jakala et al., 1999).
Subjects
The present study performed analyses in mice with a point
mutation (D79N) of the 2A-AR subtype
(MacMillan et al., 1996), which has been shown to effect a functional
knock-out of the receptor (Lakhlani et al., 1997). The
2A-AR mutant mice (C57BL/6D79NTG strain) were
created by the laboratory of Dr. Lee Limbird (Vanderbilt University,
Nashville, TN) and supplied by Dr. Brian Kobilka (Stanford University,
Stanford, CA). These animals were shown previously to lack hypotensive
2A-AR mechanisms, although they demonstrated normal blood pressure under basal conditions (MacMillan et al., 1996).
The expression of mutated 2A-AR in these mice
results in reduction of receptor density by 80% compared with levels
in wild-type mice. Furthermore, the residual
2A-AR cannot activate potassium currents or
suppress calcium currents. Thus, the D79N 2A-AR mouse serves as a functional knock-out
(Lakhlani et al., 1997). At the time that these behavioral studies
were initiated, the D79N 2A-AR mice were the
only mice altered at the 2A-AR locus to be
backcrossed against C57BL/6 mice >12 generations, permitting direct
comparison with C57BL/6 wild-type mice; 2A-AR and 2B-AR knock-out mice were not available
for examination.
The D79N 2A-AR mice were bred at Yale and were
3-6 months of age at the start of the research. Wild-type C57BL/6 mice
were purchased from The Jackson Laboratory (Bar Harbor, ME). Animals were purchased at 2 months of age and lived in the Yale University vivarium for 1-5 months before inclusion in the study to be
age-matched to mutant animals. Wild-type and mutant strains (males,
19-27 gm) were housed singly, and their food was regulated to ensure motivation on the tasks. Animals were fed a 4 gm biscuit immediately after cognitive testing; water was available ad libitum.
Animals showed a normal growth curve. Care of the animals followed the guidelines in the Guide For the Care and Use of Laboratory
Animals and was approved by the Yale Animal Care and Use Committee.
Behavioral assessment
Adaptation to testing procedures. Animals were tested
in a T maze made smaller (15 × 21 × 3 inches) to be
appropriate for testing mice. The maze was constructed of wood and
painted black, with a guillotine door separating the start box from the
main stem of the maze. Testing occurred in a small room near the colony room under normal light conditions. A sink was located on the wall to
the left of the maze, and a dustpan and broom on the wall to the right
of the maze; the maze was maintained in the same position in the room
throughout the duration of the study. All cognitive testing was
performed between 8:00 A.M. and 5:00 P.M. during the animals' light
cycle; each animal was tested by the same experimenter at the same time
of day (e.g., 11:00 A.M.) every day, Monday through Friday. Before
cognitive training, all animals were exposed to the food rewards
(halved, peeled sunflower seeds) in their home cage. Importantly, all
animals were fully habituated to the T maze and to eating food rewards
on the maze (criterion of eating 10 rewards in 8 min for two
consecutive days) and were subsequently habituated to handling
procedures on the maze (criterion of eating 10 food rewards in 5 min
while being picked up five times for two consecutive days). This was
done to minimize any affective differences between the mutant and
wild-type animals that might obscure changes in cognitive performance.
It is common for genetically altered mice to exhibit changes in
emotional responding; thus, it was particularly important that all mice
achieved the same criterion of comfort with each procedure before
continuing with the cognitive aspects of the study.
Cognitive assessment. 2A-AR mutant
mice subsequently were compared with wild-type mice on the number of
days needed to reach a criterion performance of two consecutive days of
 90% correct under 0 sec delay conditions for the delayed alternation
and spatial discrimination tasks. Half of the animals were trained on
delayed alternation first, and the other half were trained on spatial discrimination first to control for any possible order effects. In the
spatial delayed alternation task, the animal is rewarded for choosing
either the left or right arm on the first trial (not counted), but from
then on must always choose the arm not entered on the previous trial.
In contrast, in the spatial discrimination task, half the animals are
trained to always choose the left arm to receive reward, whereas the
other half are trained to always choose the right arm. In both tasks,
the animal is picked up immediately after eating the reward (or picked
up with no reward if he was incorrect) and placed in the start box
between trials. The choice point of the maze is wiped with alcohol to
prevent olfactory cues from guiding behavior. This process takes
~1-2 sec and is designated a 0 sec delay. Each daily test session
consisted of 10 trials.
For the assessment of the effects of guanfacine on delayed alternation
performance, delays were increased as needed to maintain performance of
~70% correct, thus allowing room for either improvement or
impairment with drug treatment. The delay was increased in 5 sec
intervals if a mouse performed at 90% for two consecutive testing
sessions (rarely, delay was also decreased if baseline deteriorated to
<60-70%). Thus, the delay needed to maintain baseline performance at
70% correct can be used as a measure of general performance on the task.
Drug administration
Mice were considered ready for drug administration when they had
been at their current delay for at least three test sessions and had
performed at between 60 and 70% for two consecutive test sessions.
Furthermore, a washout period of at least 7 d was required between
drug treatments. Guanfacine was dissolved in saline and was injected
(0.15 ml, i.p.) 1 hr before cognitive testing. Animals were extensively
adapted to the injection procedure before the experiment. Guanfacine
was generously provided by Wyeth-Ayerst (Princeton, NJ). An initial
pilot study identified the proper dose range for examination; doses of
0, 0.0001, 0.001, 0.01, 0.1, 1.0, or 10.0 mg/kg were injected in random
order in wild-type mice (n = 4-7) and in
2A-AR mutants (see below). Mean percentage correct ± SEM for each dose is shown in Table
1. The 0.01 mg/kg dose tended to impair
performance in wild-type mice (p > 0.1; n = 6), as has been seen occasionally in monkeys
(Arnsten et al., 1988; Franowicz and Arnsten, 1998) and is probably a
result of presynaptic drug actions reducing endogenous NE release. The
10 mg/kg dose induced sedation that interfered with testing in
wild-type and mutant mice. Only the 1.0 mg/kg dose improved the working memory performance of wild-type mice, and this dose is similar to that
which reliably improves working memory performance in young adult
monkeys as well (0.5-1.0 mg/kg). Thus, the 1.0 mg/kg dose was compared
with saline in a larger number of animals (n = 12) and
was repeated to ensure reliability of response within subjects. All
doses of guanfacine were tested in a large sample of
2A-AR mutants (n = 10) to
ensure that no other dose of guanfacine was effective (Table 1).
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Table 1.
Preliminary data showing mean percent correct on the
delayed alternation task after administration of guanfacine
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Statistics
Simple comparisons between the wild-type and mutant mice were
analyzed with an independent t test
(Tind). Delay achieved over time was analyzed by
ANOVA with a mixed design: a within-subjects factor of time (25th vs
50th test session) and a between-subjects factor of
2A-AR mutation (wild type vs
2A-AR mutation). Statistical analyses were
performed with Systat (Evanston, IL) software.
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RESULTS |
Habituation to test procedures
The mice were initially adapted to the maze, food rewards, and
handling procedures to minimize contamination of affective influences
on cognitive assessment. Animals were required to reach criterion
levels of responding before continuing to the next level of the study.
These procedures are particularly important for mice, given their
neophobic response to novel environments and procedures. The
2A-AR mutants were not different from
wild-type mice in their time to habituate to eating food rewards in the maze (wild-type mice, n = 6, 4.8 ± 0.9 d to
reach criterion; 2A-AR mutant mice,
n = 6, 3.3 ± 0.7 d to reach criterion;
Tind, p > 0.1);
however, they were markedly slower to habituate to handling procedures
in the maze (Fig. 1A)
(Tind; p < 0.002).
These results are consistent with recent data suggesting that mice with
genetically altered 2A-AR can show heightened
signs of anxiety (Schramm et al., 2001), whereas in contrast, those
with reduced 2C-AR exhibit decreased response
to stress (Sallinen et al., 1999).
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Figure 1.
A comparison of the performance of wild-type
versus 2A-AR mutant mice in the time needed to habituate
to the test procedures and to learn the cognitive tasks. The graph
illustrates the mean ± SEM days to criterion for habituation to
handling in the T maze (A), spatial
discrimination performance (reference memory, control task)
(B), and spatial delayed alternation performance
with 0 sec delays (working memory, PFC task) (C).
Criterion for each condition is described in Materials and Methods.
Solid bars, Results for wild-type (WT) mice; open
bars, for 2A-AR mutant mice
(2A). 2A-AR mutant mice took
significantly longer to habituate to the testing conditions but
subsequently learned both tasks at normal rates.
**Significantly different from wild-type animals,
p < 0.002, n = 6.
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Acquisition of the cognitive tasks
Once habituated to the maze and handling procedures, the mice were
trained in the T maze on either the spatial working memory task,
delayed alternation, or the reference memory task, spatial discrimination. There were no significant differences between the
2A-AR mutants and the wild-type controls in
the time needed to learn either the delayed alternation task (0 sec
delays; Tind, p = 0.92) (Fig. 1C) or the spatial discrimination task
(Tind, p = 0.82) (Fig.
1B) to criterion levels of responding. Thus, learning was unaffected by the mutation of the
2A-AR.
Delay achieved on the delayed alternation task
A second group of animals was used to evaluate the effects of the
2-AR agonist guanfacine on the delayed
alternation performance of the 2A-AR mutant
versus wild-type mice (n = 12). After habituation to
the maze as described above, the mice were trained on the delayed alternation task, and a stable baseline of performance was established for assessment of drug effects on working memory performance. Delays
were increased as needed (see Materials and Methods) to maintain
performance of ~70% correct, thus allowing room for either improvement or impairment with guanfacine treatment. Thus, the delay
needed to maintain baseline performance at 70% correct can be used as
a measure of general performance on the task.
Wild-type mice were able to withstand significantly greater delays than
the mutant mice, as shown in Figure 2,
comparing mice at the 25th and 50th testing sessions. Although all mice
were able to withstand increasing delays as the study progressed
(ANOVA; within-subjects effect of time;
F(1,22) = 15.21; p = 0.001), there was a highly significant effect of the
2A-AR mutation on the delay needed to maintain
baseline performance at 70% correct (between-subjects effect of the
2A-AR mutation;
F(1,22) = 27.23; p < 0.0001). The effects of the mutation became increasingly evident over
time (significant interaction between the effects of the mutation and time: F(1,22) = 12.57;
p = 0.002). Thus, the differences between the mice had
already emerged by the 25th test session (mean ± SEM delay
needed: wild-type, 5.0 ± 2.2 sec; 2A-AR
mutants, 0 ± 0 sec; p < 0.03) but were more
evident by the 50th test session (mean ± SEM delay needed:
wild-type, 13.7 ± 2.1 sec; 2A-AR,
0.4 ± 0.4 sec; p < 0.00001). Thus, by the 50th
test session, no 2A-AR mutant mouse had
experienced a delay >5 sec, whereas the majority of wild-type mice
were able to show solid baseline performance with delays of 15-20 sec.
These data indicate that the 2A-AR mutant mice
have measurably poorer performance when working memory abilities are
challenged.
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Figure 2.
Comparison of the abilities of the wild-type
versus 2A-AR mutant mice on the delayed alternation
task, a test of working memory, behavioral inhibition, and attention
regulation. Results represent the mean ± SEM delay needed to
achieve baseline performance of ~70% correct after the 25th and 50th
daily test sessions of the delayed alternation task. Solid
bars, Results for wild-type mice; open bars, for
2A-AR mutant mice. 2A-AR mutant mice
needed significantly lower delays than wild-type controls to perform at
70% correct. *Significantly different from wild-type
animals, p < 0.03; **significantly
different from wild-type animals, p < 0.00001;
n = 12.
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Response to the 2-AR agonist guanfacine
The effects of the 2-AR agonist
guanfacine were compared in the wild-type and
2A-AR mutant mice after establishment of
stable baseline performance. Pilot studies of a wide range of
guanfacine doses indicated that the 1.0 mg/kg dose was appropriate for
cognitive enhancement in mice. Thus, the 1.0 mg/kg dose was compared
with saline in wild-type versus 2A-AR mutant
mice. The results are shown in Figure 3.
A two-way ANOVA with a between-subjects factor of
2A-AR mutation (wild-type versus
2A-AR mutation) and a within-subjects factor
of drug (saline vs guanfacine) found a significant effect of
2A-AR mutation
(F(1,19) = 5.73; p = 0.027), no significant overall effect of drug
(F(1,19) = 1.39; p = 0.25), and a significant 2A-AR mutation by drug interaction
(F(1,19) = 5.021; p = 0.037). Thus, guanfacine significantly improved delayed alternation
performance in the wild-type mice (p = 0.04;
n = 12) but had no effect on the
2A-AR mutant mice (p = 0.46; n = 12). Wild-type mice were improved by 1.0 mg/kg guanfacine irrespective of whether they received guanfacine early
in the study when their delays were short (e.g., 0 sec) or later in the
study when their delays were longer. Thus, guanfacine improved
performance in WT mice whether their delays were 0 sec (saline 65%;
GFC 77%; p = 0.02), 15 sec (saline 74%; GFC 85%;
p = 0.02), or 20 sec (saline 68%; GFC 87%; p = 0.05) at the time when they received guanfacine. A
similar pattern has been observed in monkeys, in which guanfacine
improves spatial working memory performance on trials with either short or long delays (Franowicz and Arnsten, 1998). Other doses of guanfacine were without effect in the 2A-AR mutant mice
(Table 1).
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Figure 3.
The effects of saline versus the
2-AR agonist guanfacine (1.0 mg/kg) in wild-type mice
(left) versus 2A-AR mutant mice
(right) performing the delayed alternation task, a test
of working memory, behavioral inhibition, and attention regulation.
Guanfacine improved performance in the wild-type mice but had no effect
in the 2A-AR mutant animals. Results represent mean ± SEM percentage correct on the delayed alternation task.
*Significantly different from saline, p < 0.04; n = 12.
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DISCUSSION |
Studies of rats, monkeys, and human beings have found that
2-AR agonists, such as guanfacine, improve the
cognitive functions of the PFC but have no effect on or impair the
cognitive abilities of posterior cortical or subcortical regions. For
example, systemic administration of 2-AR
agonists to rats, monkeys, or human beings enhances performance of
tasks that require working memory, planning, behavioral inhibition, and
attention regulation and depend on the integrity of the PFC (Arnsten
and Goldman-Rakic, 1985; Jackson and Buccafusco, 1991; Arnsten and
Contant, 1992; Carlson et al., 1992; Coull et al., 1995; Rama et al.,
1996; Steere and Arnsten, 1997; Jakala et al., 1999; O'Neill et al.,
2000). These beneficial effects are dissociable from the hypotensive
and sedating actions of these compounds (Arnsten et al., 1988) and are
consistent with the known role of NE in attention regulation (Carli et
al., 1983). In contrast, the learning and memory abilities of medial
temporal lobe (Arnsten and Goldman-Rakic, 1990; Sirviö et al.,
1991; Genkova-Papazova et al., 1997) and parietal cortex (Witte and
Marrocco, 1997) are unaffected or even impaired by
2-AR stimulation. Thus, the beneficial effects
on cognitive function appear to be selective to the PFC.
It is likely that the improved performance induced by guanfacine in the
present mouse study similarly reflects enhanced PFC cognitive function.
Although guanfacine was administered systemically and thus influenced
the entire neuroaxis, studies in rats and monkeys have demonstrated
that these beneficial effects of 2-AR agonists
arise from direct actions in the PFC. In monkeys, infusion of the
2-AR agonist guanfacine directly into the PFC
produces a delay-related improvement in working memory performance (Mao et al., 1999), and similar beneficial effects have been seen with agonist infusion into the PFC of aged rats (Tanila et al., 1996). Conversely, infusion of the 2-AR antagonist
yohimbine produces a delay-related impairment in performance (Li and
Mei, 1994), emphasizing the importance of endogenous NE stimulation of
these receptors. At the cellular level, either systemic or
iontophoretic application of an 2-AR agonist
increases the delay-related activity of PFC neurons (Li et al., 1999),
the electrophysiological measure of working memory and behavioral
inhibition (Funahashi et al., 1993). Conversely, the iontophoretic
application of an 2-AR antagonist decreases
the delay-related activity of PFC neurons (Sawaguchi, 1998; Li et al.,
1999), indicating that endogenous NE release has a critical effect on
PFC neuronal responding. The importance of
2-AR stimulation to PFC function has been
corroborated in imaging studies in which systemic administration of the
2-AR agonist guanfacine increases regional
cerebral blood flow in the PFC of both monkeys and human beings (Avery
et al., 2000; Swartz et al., 2000). Given the consistency of these
findings and the clinical use of guanfacine to treat PFC cognitive
disorders, it was of great interest to determine the
2-AR subtype underlying these important
beneficial effects of NE and 2-AR agonists on PFC function.
The present study found that mutation of the
2A-AR significantly weakened working memory
performance on the delayed alternation task and prevented cognitive
enhancement by guanfacine. Mice with mutations of this receptor were
not able to achieve the longer delays acquired by wild-type mice,
indicating weaker PFC regulation of behavior. Poorer achievement on the
delayed alternation task by the mutant mice is unlikely to be accounted
for by nonspecific changes in performance or affective variables,
because the 2A-AR mutant mice learned the task
at a rate similar to that of wild-type mice under 0 sec delay
conditions and were able to perform the spatial discrimination task
similarly to wild-type animals. These findings are consistent with
previous studies in which 2A-AR stimulation
did not improve learning (Sirviö et al., 1991). Special care was taken to minimize any affective influences on cognitive assessments, because emotional changes are common in mouse mutants and
have been specifically identified in mice with altered
2A-AR (Schramm et al., 2001). Mice were
carefully adapted to all potentially stressful procedures to set
criteria to ensure that mutants and wild-type animals were equally
comfortable with manipulations such as handling. After these adaptive
measures, mice were indistinguishable in their behavior in the maze,
with the exception that mutant mice were unable to achieve the longer
delays acquired by wild-type animals. This profile is consistent with
weaker PFC regulation of behavior. Deficits on working memory tasks
have been observed in other genetically altered mice, e.g., those with
overexpression of the mutant human amyloid precursor (Dodart et al.,
1999). However, these working memory deficits occurred in the
constellation of broader cognitive deficits, i.e., impaired reference
memory and object recognition memory, consistent with widespread
cortical and hippocampal plaque deposition (Dodart et al., 1999). In
contrast, the present data provide the first evidence of a genetic
mutation selectively impairing performance of a working memory task
dependent on the PFC and emphasize the importance of
2A-AR stimulation for the strength of working
memory function. These findings echo those observed in monkeys with
blockade of 2-AR in PFC by local infusions of
yohimbine, who exhibited markedly impaired working memory performance
at delays as short as 4 or 6 sec (Li and Mei, 1994) and weakened
delay-related neuronal activity in the PFC (Sawaguchi, 1998; Li et al.,
1999). The present findings identify the molecule in which endogenous
NE acts to increase delay-related firing and thus to strengthen PFC
regulation of behavior. These findings represent the first, stringent
dissociation of the 2-AR subtype contributions
to higher cortical function. Because the functions of the PFC are
fundamental to many of the highest-order cognitive abilities in humans,
identification of a molecule critical to the functional integrity of
the PFC is of wide-ranging significance.
Weakened spatial working memory performance in the mutant mice may not
be solely a result of loss of a beneficial, postsynaptic 2A-AR substrate for NE actions in the PFC but
also of a disinhibition of detrimental factors. For example, the mutant
mice also have lost much presynaptic regulation of NE release and most
likely have excessive NE release (Trendelenburg et al., 2001). We have shown that such conditions during stress exposure impair working memory
via stimulation of 1-AR (Birnbaum et al.,
1999). This possibility could be tested in the future by determining
whether an 1-AR antagonist improves the
performance of mutant mice but not WT animals under nonstress
conditions. However, 1-AR may have been
downregulated as a consequence of sustained stimulation, in which case
this factor may not contribute to working memory impairment. An
additional possibility is that loss of the
2A-AR leads to an imbalance between
2A-AR and 2C-AR
subtypes that is harmful. Cognitive deficits on non-PFC tasks have been
observed in mice overexpressing the 2C-AR
subtype (Bjorklund et al., 1998, 2000), and an imbalance between these
subtypes may similarly alter PFC function. Finally, it is possible that
differences in early environmental rearing conditions could contribute
to differences in working memory abilities as adults, but changes of
this kind probably would have been expressed in our measures of spatial learning as well (Liu et al., 2000).
The second major finding of this study was that administration of the
2-AR agonist guanfacine significantly improved
the working memory performance of wild-type mice but had no effect on
the 2A-AR mutant mice. These results contrast
with those found in mice with a genetic alteration of the
2C-AR, which showed normal improvement with
2-AR agonist treatment on a spatial working memory task (Tanila et al., 1999). Together, these data demonstrate that stimulation of the 2A-AR subtype
underlies the beneficial effects of 2-AR
agonists on PFC function.
Guanfacine is currently being used to treat adults and children with
ADHD (Chappell et al., 1995; Horrigan and Barnhill, 1995; Hunt et al.,
1995; Scahill et al., 2001; Taylor and Russo, 2001), and double-blind,
placebo-controlled trials have confirmed that guanfacine treatment
enhances performance of PFC tasks in these patients (Scahill et al.,
2001; Taylor and Russo, 2001). Preliminary research also suggests that
guanfacine may benefit other neuropsychiatric disorders that involve
PFC dysfunction, such as posttraumatic stress disorder (Horrigan, 1996)
and schizophrenia (Friedman et al., 1999). The data from this study, in
combination with previous research in rats, monkeys, and human beings,
identifies the 2A-AR as the molecular
substrate for the therapeutic actions of guanfacine. However, given
that the 2A-AR also mediates many of the
hypotensive effects of these agents, it will not be possible to develop
2A-AR agonists devoid of hypotensive side effects.
A rekindling of interest in NE mechanisms underlying neuropsychiatric
disorders such as ADHD has begun to emerge in recent years (Biederman
and Spencer, 2000). For example, whereas previous research has often
emphasized the contribution of dopaminergic mechanisms in the actions
of stimulants such as methylphenidate and D-amphetamine,
recent data indicate that the lower doses of stimulants used to treat
ADHD patients preferentially release NE in rat brain (Kuczenski and
Segal, 2001). In concert with this basic finding, selective NE reuptake
blockers are now being developed for the treatment of ADHD, and this
avenue appears promising (Spencer et al., 1998; Biederman and Spencer,
2000). The data from the present study indicate that the therapeutic
actions of these agents probably involve facilitation of endogenous NE
stimulation of 2A-AR in the PFC. Thus, either
endogenous NE or guanfacine-like compounds stimulate
2A-AR in the PFC, which leads to increased delay-related activity of PFC neurons, which results in stronger PFC
regulation of behavior and reduced symptoms of impulsivity, distractibility, and disorganization. These data represent a rare example whereby one can establish a direct connection between highly
specified drug actions in the brain and therapeutic efficacy in mental disorders.
| |
FOOTNOTES |
Received March 26, 2002; revised June 17, 2002; accepted June 17, 2002.
This work was supported by United States Public Health Service (USPHS)
Grant R37-AG-06036 to A.F.T.A.. The mice were created with the support
of USPHS Grant HL-43671 to L.E.L. We thank Tracy White, Lisa
Ciavarella, and Sam Johnson for their invaluable technical expertise.
Correspondence should be addressed to Dr. Amy F. T. Arnsten,
Section of Neurobiology, Yale University School of Medicine, New Haven,
CT 06510. E-mail: amy.arnsten{at}yale.edu.
| |
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TOP
ABSTRACT
INTRODUCTION
