in baseline performance and methylphenidate response on measures of attention,
impulsivity and hyperactivity in a Visual Stimulus Position Discrimination Task
Panayotis K. Thanosa,b,c,⁎, Iliyan Ivanovd,1, John K. Robinsonc,1, Michael Michaelidesa,c, Gene-Jack Wanga,
James M. Swansone, Jeffrey H. Newcorne, Nora D. Volkowb
aLaboratory of Neuroimaging, NIAAA, NIH, Dept of Health and Human Services, Bethesda, MD 20892, USA
bBehavioral Pharmacology and Neuroimaging Lab, Department of Medicine, Brookhaven National Laboratory, Upton, NY 11973, USA
cBiopsychology Area, Dept. of Psychology, Stony Brook University, Stony Brook, NY 11794, USA
dDept. of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA
eUniversity of California, Irvine, Irvine, California, USA
a b s t r a c t a r t i c l e i n f o
Received 18 December 2008
Received in revised form 16 September 2009
Accepted 24 September 2009
Available online 8 October 2009
The spontaneously hypertensive rat (SHR) is a widely accepted rodent model of Attention Deficit/Hyperactivity
Disorder(ADHD),andmethylphenidate(MP)isa centralnervous systemstimulantthathas beenshown tohave
a dose-related positive effect on attention task performance in humans with ADHD. The current study was
Stimulus Position Discrimination Task (VSPDT) as well as of the responsiveness of the two rat strains to MP
treatment. The rats were initially trained on the VSPDT, in which a light cue was presented randomly at three
different cue-light intervals (1 s, 300 ms and 100 ms) over one of two levers, and presses on the lever
corresponding to the light cue were reinforced with a food pellet. Once rats reached stable performance, the
treatment phase of the study began, during which they received daily intraperitoneal (IP) injections of saline,
2 mg/kg, 5 mg/kg, and 10 mg/kg of MP in a randomized order immediately prior to being tested on the VSPDT.
Baseline performance accuracy on the VSPDT did not differ between the groups. Furthermore, a striking strain
dissociation was evident in the response of the two strains to treatment; VSPDT performance was substantially
disrupted by the 5 and 10 mg/kg dose in the WKY rats but only mildly in the SHR rats. Response omissions were
also increased only in WKY rats. Finally, both strains had increased locomotor activity in the operant chamber
following MP treatment. These findings point to an important difference in response tendency to MP in the two
strains that supports a view that a critical difference between these strains may suggest neurochemical and
neuroadaptive differences associated with the behavioral impairments of ADHD.
© 2009 Published by Elsevier Inc.
Attention Deficit Hyperactivity Disorder (ADHD) is a frequently
occurring neuropsychiatric disorder characterized by hyperactivity,
impulsivity and inattention (Mannuzza et al., 1993), which begins in
early childhood and, in many cases, persists into adolescence and
adulthood (Kessler et al., 2006; Mannuzza et al., 1993). Epidemiologic
data using comparable assessment instruments and definitions of the
disorder indicate the prevalenceto be approximately 5–8% worldwide
(Kessler et al., 2006; Polanczyk et al., 2007; Resnick, 2005; Schneider
and Eisenberg, 2006; Wilens et al., 2002).
Several rodent models of ADHD have been proposed (Sagvolden
the general population (Puumala et al., 1996), animals reared in social
isolation (Jones et al., 1991), or those exposed to a variety of
environmental manipulations (Collins et al., 2004; Dell'Anna et al.,
1993; Diaz-Granados et al., 1994; Holene et al., 1998). There are also
different genetically-derived models (Mook et al., 1993; Myers et al.,
1982;Sagvolden etal.,1992).Ingeneral,avalidanimalmodel forADHD
should approximate the fundamental behavioral characteristics of
ADHD (face validity), conform to a theoretical rationale for ADHD
and therapeutic interventions (both behavioral and pharmacological),
not previously examined in human populations (predictive validity)
(Sagvolden et al., 2005).
One genetically-derived model, the spontaneous hypertensive rat
(SHR) (Mook et al., 1993; Myers et al., 1982; Sagvolden et al., 1992)
capitalizes on behaviors exhibited by a strain with a particular genetic
Pharmacology, Biochemistry and Behavior 94 (2010) 374–379
⁎ Corresponding author. Behavioral Pharmacology and Neuroimaging Lab, Department
of Medicine, Brookhaven National Laboratory, Upton, NY 11973, USA.
E-mail address: firstname.lastname@example.org (P.K. Thanos).
1Contributed equally to the manuscript.
0091-3057/$ – see front matter © 2009 Published by Elsevier Inc.
Contents lists available at ScienceDirect
Pharmacology, Biochemistry and Behavior
journal homepage: www.elsevier.com/locate/pharmbiochembeh
mutation (i.e., SHR), which is then contrasted with the progenitor
wild-type strain, the Wistar–Kyoto (WKY), as controls. SHR are more
active than their WKY counterparts (Berger and Sagvolden, 1998;
Hard et al., 1985; Hendley et al., 1985; Mook and Neuringer, 1994;
Wultz et al., 1990), and tend to prefer immediate smaller rewards
rather than delayed larger rewards (Mill et al., 2005). In addition, they
display little reactivity to novel environments (Delini-Stula and Hunn,
1985; Hard et al., 1985; Sutterer et al., 1988) and have specific
learning impairments such as that SHR require a longer time interval
to learn a new task (Low et al., 1984) or tend to repeat particular
sequences of ineffectual responses (Mook et al., 1993).
Despite the considerable appeal of this model, some concern has
been raised thatthese apparentbroad ranges of deficits may result from
Wistar–Kyoto animals often used as the control subjects are hypoactive
rat as a model for deficits in sustained attention in ADHD, leaving this
aspect of the model underevaluated. The studies that report deficits in
sustained attention, in some cases remediated with psychostimulants
(e.g. Sagvolden and Xu, 2008), employed free-operant schedules of
reinforcement that are highly influenced by changes in response
tendency, especially during signaled extinction components which
could readily be interpreted as impairments due to impulsivity rather
than inattention (see Sagvolden,2000).Only one report in theliterature
employed a sustained attention task that employed a visual signal
detection procedure (the five-choice serial reaction time task, 5CSRTT)
where response accuracy could be assessed independently of response
tendency (van den Bergh et al., 2006). These authors reported no strain
differences in response accuracy between SHR and WKY rats in any
measures of baseline performance or in strain responsiveness to 0.1–
testing procedures, the apparent good construct and face validity of the
SHR model as a model of the attention deficits in ADHD would be
seriously undermined. Because of the importance of this issue for the
SHR rat model of ADHD, the present work was conducted as an
important systematic test of the replicability of these results in the
5CSRTT, to produce more confidence in the certainty of that finding.
Therefore, we employed another procedure for the examination of
performance differences in a signal detection procedure (the Visual
Stimulus Position Discrimination Task, VSPDT) in which the detectabil-
ity of the visual stimulus varied within-session (Presburger and
Robinson, 1999), and detection, motivation and motor influences
could be dissociated. This procedure has a long history of use as a
behavioral model of visual signal detection [(Blough, 1967; Bushnell,
but also requires some degree of sustained attention across the session.
One hypothesis that follows from the observation that humans with
ADHD show enhanced distractability would be that (1) SHR would be
less accurate and omit more detection responses than WKY rats in
baseline signal detection and (2) that MP pre-treatment should
demonstrate dose-dependent improvements in these aspects of
performance. However, an alternative hypothesis, based on a previous
report (van den Bergh et al., 2006), would be that the SHR and WKY
fail to be restorative. While this alternative hypothesis would
underminethecasefor theSHRto serve asa comprehensive simulation
of ADHD, it would alsobe useful in articulatingand challengingsome of
the assumptions of the often made SHR vs. WKY comparison.
Male adolescent SHR [n=9] and WKY [n=9] rats, approximately
5–6 weeks of age and 70–100 g in weight, were obtained from Charles
River Laboratories (Wilmington, MA) for use in this study. Once the
rats arrived they were individually housed for the remainder of the
study in clear acrylic cages with wire covers under standard
laboratory conditions (22±2 °C, 50±10% relative humidity). A
12 h/12 h light/dark cycle was used, with lights on at 0900 and off
at 2100. All rodents received 20 g of food per day (Rodent Diet 5001,
PMI, Richmond, Indiana, USA) and water was available ad-libitum.
Experiments were conducted in conformity with the National
Academy of Sciences Guide for the Care and Use of Laboratory
Animals (NRC, 1996) and Brookhaven National Laboratory Institu-
tional Animal Care and Use Committee protocols.
MP hydrochloride, racemic mixture; (Sigma, St. Louis, MO) was
dissolved in physiological saline and injected intraperitonealy (IP) at
the following doses: 2 mg/kg, 5 mg/kg, and 10 mg/kg.
Six identical clear acrylic operant test chambers were used — each
measuring 32×25×33 cm and enclosed in a sound-attenuation
chamber (Coulbourn Instruments, Allentown, PA, USA). Cage floors
were constructed of stainless steel horizontal bars spaced 1.2 cm
apart. Test cages were equipped with a food trough located between
two response levers (both active) with lights above each lever.
Locomotor activity was assessed using an infrared monitor affixed to
the ceiling of each cage as well as through direct observation by way
of pin-hole video cameras connected to each testing cage. All test data
were collected from the test chamber and recorded using Graphic
State software. Lever presses, number of pellets dispensed, and
locomotor counts were all recorded in each session. Each rat was run
for one 30 minute session/day starting at 10:30am.
2.4.1. The VSPDT
Rats were food-deprived to 85% of free-feeding body weight over a
period of 7–10 days then trained to press the lever situated directly
below a cue light after the light turned on in return for a 45 mg food
pellet (Bioserv, NJ, USA). The light stayed on until rats pressed the
correct lever appropriately. Rats were trained until they consistently
made at least 80% correct lever presses within a 30 minute session, a
threshold which typically took 2–3 sessions to achieve. After rats were
the food pellet only by pressing the correct lever (i.e., when signaled by
the cue light), but this time the light stayed on for only 1 s (Fig. 1a).
When the animals reached greater than 80% accuracy in correct lever
presses they were again moved to a new protocol, in which the light
above one of the two levers would light up for different durations of
time: 1 s, 300 ms, and 100 ms. The sequence of stimulus duration was
was set at 80%, an intermediate value capable of optimally detecting
enhancement of impairment of performance for 3 consecutive days
before the rats could begin to receive drug [and the intertrial interval
(ITI) was fixed at 10 s].
2.4.2. MP treatment and the VSPDT
Once the performance criteria were reached, animals received a
saline treatment for 3 consecutive days to evaluate performance in a
drug-free state to overcome potential performance disruptions due to
injection treatment. In the treatment phase the animals were treated
with three different concentrations of MP for 1 day separated by 3 days
of saline washout. The treatment order was randomly assigned using a
Latin square design (Fig. 1b).
P.K. Thanos et al. / Pharmacology, Biochemistry and Behavior 94 (2010) 374–379
2.5. Measures of behavioral performance and statistics
We examined the following behavioral measures: i) Response
accuracy: Response accuracy has been shown to be a function of two
factors (Echevarria et al., 2005). The first is a stimulus property, dis-
criminability, which is demonstrated by decreased baseline accuracy
as the stimulus duration is decreased. The second property of the
response accuracy measure is in detecting subtle changes in motiva-
tional state, in that it has been shown that reward devaluation
procedures reduce accuracy at the short stimulus durations (100 and
300 ms). ii) Response Omissions: Baseline response omissions increase
as stimulus duration is decreased, indicating some sensitivity to
stimulus discriminability. However, the experimental devaluation of
the reinforcer results in a strong increase in omissions at all stimulus
durations, indicating that this measure is primarily sensitive to the
motivational aspect of sustained performance, including direct (e.g.
change in deprivation conditions) and indirect (e.g. enhanced
motility) effects on reward value. iii) Impulsive responding unrelated
to task performance: This measured intertrial interval (ITI) responses
and is indicative of failure of non-consequential response suppression
during signaled non-reinforcement periods. iv) Locomotor activity
(i.e., total number of beam breaks detected during a session): Given
the familiarity of the environment for the animals after the extensive
pretraining, this measure is probably best indicating general arousal
level of the animals during the session.
Measures were initially examined using three-way repeated
measures ANOVA with treatment condition, stimulus duration, and
for significant main effects and interactions of theoretical interest. The
Huynh–Feldt reduction in degrees of freedom was applied to adjust for
violation of assumptions in the repeated measures ANOVA. Matched
sample t-tests were used to follow up on significant ANOVA results of
interest, and where significant are reported in the figures. All data were
analyzed using SPSS software (SPSS Inc. Chicago, IL, USA). Specific
for baseline levels.
3.1. Signal detection accuracy
The strains did not differ significantly [F(1,16)=2.607, pN.05]
when compared in the saline treatment only, but there was a
significant difference in cue interval [F(2,32)=89.437, pb.0005;
Fig. 2.1], reflecting more correct responses in longer intervals. There
was also a significant interaction [F(2,32)=6.944, p=.01] reflecting
stronger cue interval differences in SHR [F(2, 16)=53.951, pb.0005]
than WKY [F(2,16)=36.314, pb.0005]. Within-session performance
accuracy did not differ between the two strains (Fig. 2.2).
When all treatments were considered (Fig. 3), there were
significant main effects of strain [F(1, 16)=60.183, pb.0005],
reflecting more correct responses in SHR than WKY, stimulus duration
[F(1.367, 21.872)=103.600, pb.0005], reflecting more correct
responses in longer intervals, and treatment condition [F(2.636,
42.176)=40.011, pb.0005], reflecting fewer correct responses with
higher MP doses. There were significant interactions for cue interval
X strain [F(1.367, 21.872)=4.811, pb.034] and treatment X strain
[F(2.636, 42.176)=26.780, pb.0005], reflecting stronger differ-
ences in both for WKY than SHR. There was a non-significant trend
for the interaction of strain X cue interval X treatment [F(4.795,
76.728)=1.974, p=.095], reflecting a significant cue interval X
treatment interaction for WKY [F(2.78, 22.26)=37.257, pb.0005]
but not for SHR.
3.2. Response omissions
There were significant main effects (Fig. 4.1) of strain [F(1, 16)=
82.310, pb.0005], stimulus duration [F(1.709, 27.351)=4.937, pb.019]
and treatment [F(2.076, 33.210)=19.379, pb.0005]. The two way
Fig. 1. Timeline of experiment. The duration of the food and task training including the
days when animals' baseline performance was recorded are shown on the upper panel.
The duration of the treatment phases for the low, medium and high doses are shown on
the lower panel.
Fig. 2. (2.1)WKY and SHR performance in different light cue conditions during the
vehicle treatment. The three light cues (100 ms, 300 ms, 1 s) are shown on the X axis
and the percent correct responses are shown on the Y axis. The two line graphs
represent the choice accuracy for SHR and WKY rats as a function of stimulus cue
duration. No difference was evident between the groups in the baseline condition.
(2.2) Within-session data comparing SHR and WKY rats at the 100 ms signal for the
saline treatment session prior to drug treatment. A slight warm-up effect and end-of-
session drop off effect is revealed, but no differential accuracy between the two groups
at the final session blocks, as might be predicted if the two groups differed in vigilance
P.K. Thanos et al. / Pharmacology, Biochemistry and Behavior 94 (2010) 374–379
interaction was significant for treatment X strain [F(2.076, 33.210)=
18.650, pb.0005]. No significant strain X cue interval, cue interval X
Separate analyses by strain also revealed a significant main effect of
treatment, but only for WKY rats [F(2.194, 17.550)=19.339, pb.005].
There were no significant main effects of cue interval for either strain,
and no significant cue interval by treatment interaction.
The significant findings from between-treatment comparisons are
summarized in Fig. 4.1, and show that in all three stimulus durations
the treatment effect for WKY was larger than for SHR (larger increase
of number of omissions with higher dose treatments).
3.3. Intertrial interval responses
There was a significant main effect (Fig. 4.2) for strain [F(1, 16)=
12.173, pb.003] but not treatment. There was also a significant
interaction for strain X treatment [F(2.482, 39.718)=8.529, pb.005].
Within-strain analyses revealed that the effect of treatment was
significant for WKY [F(3, 24)=13.600, pb.005] but not SHR rats.
Similarly, pair-wise comparisons in SHR rats showed no significant
difference in ITI by treatment condition. In contrast, in WKY the
higher dose treatments (5 and 10 mg/kg) significantly decreased the
intertrial interval responses compared to both vehicle and the 2 mg/
kg treatment. However, significant differences in WKY performance
should be interpreted with caution since high dose treatments also
produced an overall decrease in absolute number of responses to all
light cues (i.e. response omissions).
Fig. 3. WKY and SHR correct lever presses indifferent light cue conditions with different
treatments. The four dose treatments (vehicle, 2 mg/kg, 5 mg/kg, 10 mg/kg) are shown
on the X axis and the percent correct responses are shown on the Y axis. The line graphs
represent the correct lever presses during the three light cues (100 ms, 300 ms, 1 s) for
SHR (3.1) and WKY (3.2) rats. MP treatments with 5 mg/kg and 10 mg/kg produced
pronounced choice accuracy deficits at all stimulus duration for the WKY rats (lower
panel) but only mild impairment for the SHR rats (top panel).
Fig. 4. Behavioral measures for WKY and SHR with different treatments. 4.1. Response
omissions. The four dose treatments (vehicle, 2 mg/kg, 5 mg/kg, 10,g/kg) are shown on
the X axis. The percent omissions are shown on the Y axis. MP treatments with 5 mg/kg
and 10 mg/kg produced marked increase in response omissions for the WKY rats but
not for the SHR rats. Due to the fact that the omission curves for each strain were very
similar across light cue conditions, the four treatments were collapsed in a single line
graph for each strain. 4.2. ITI responses. The four dose treatments (vehicle, 2 mg/kg,
5 mg/kg, 10 mg/kg) are shown on the X axis. The ITI responses are shown on the Y axis.
The MP treatments with 5 mg/kg and 10 mg/kg produced significant decreases in non-
reinforced ITI responses for the WKY rats and non-significant increase for the SHR rats.
4.3. Locomotor activity. The four dose treatments (vehicle, 2 mg/kg, 5 mg/kg, 10,g/kg of
MP) are shown on the X axis. The locomotion measures are shown on the Y axis. MP
treatments magnified the baseline activity difference between the two stains
represented by the line graphs for the WKY and the SHR rats.
P.K. Thanos et al. / Pharmacology, Biochemistry and Behavior 94 (2010) 374–379
3.4. Locomotor activity during VSPDT
There were significant main effects (Fig. 4.3) for both strain
[F(1, 16)=42.967, pb.0005] and treatment [F(2.593, 16)=14.727,
pb.0005], but there were no significant strain X treatment interactions.
Overall, SHR rats exhibited higher mean locomotor activity than WKY
rats at baseline (t=6.238, df=16, pb.0001). Within-strain analyses
revealed significant main effects of treatment for both SHR [F(2.182,
17.452)=8.446, pb.002] and WKY [F(2.481, 19.844)=8.769, pb.002]
rats. Pair-wise comparisons within the SHR group found a significant
increase in locomotor activity with the 2, 5 and 10 mg/kg doses
compared to saline. For WKY, all treatments also increased locomotor
activity compared to saline. The data also indicates that treatment
condition produced similar patterns of change for both strains
(see Fig. 4.3). All three treatments increased locomotor activity for
both strains compared to vehicle, but not in a dose-linear fashion; the
and 10 mg/kg dose treatments.
baseline differences between the SHR and WKY as being primarily
attention. Furthermore, they reveal a strong differential sensitivity of
the WKY rats to MP treatment in motor and sustained attention
parameters of the VSPDT task. These are discussed in detail below.
4.1. Baseline performance of SHR and WKY
Baseline performance (e.g. vehicle condition) on the VSPDT
showed no significant differences on response accuracy in the most
demanding (and thereby revealing) 300 and 100 ms light stimulus
durations, and on intertrial interval responses at all three cue
durations (Fig. 2.1) as well as within-session accuracy patterns
(Fig. 2.2). These findings do not support strain-specific differences
between SHR and WKY rats on sustained attention and are consistent
with those reported previously using the five-choice serial reaction
time task (van den Bergh et al., 2006) and a simple visual
discrimination procedure (Sagvolden and Xu, 2008). However, this
later report, that also used a sustained attention test that required
detection (and remembering) the position of an unsignaled concur-
rent random interval 180 s-extinction schedule, showed poorer
performance in SHR than WKY rats. The extending periods on non-
reinforcement of this test may have been a critical difference. Taken
together, these findings suggest that frequent cues and reinforcers
serve to reduce the potential for distraction of the SHR rats, and that it
is under conditions of extended periods where attention is required
but little change in environmental conditions occur that their deficits
are best revealed (Alsop, 2007).
4.2. MP effect on SHR and WKY performance on VSPDT
In contrast to the limited baseline differences, MP treatment
revealed striking dissociations of effects on several measures. Overall,
the choice accuracy and response omissions measures. SHR rats were
only mildly impaired in response accuracy compared to the WKY rats,
doses at all retention intervals. It certainly could be argued that if one
assumed that baseline choice accuracy performance and response
omissions were at a performance ceiling at the time of drug treatment,
then this lack of a MP-induced impairment in choice accuracy and
response omissions represents a positive validation of the effectiveness
Sprague–Dawley rats given a more extended period of pretraining in
this exact procedure achieve choice accuracy levels at least 10–15%
more modest performance criterion prior to treatment. Therefore, it
have been detected. This argument suggests that it would be
worthwhile to further evaluate the SHR vs. WKY strains in behavior
that are not present in the literature.
Both strains showed modestly enhanced locomotion, but this only
added to the baseline difference between the strains and did not reveal
an interaction. MP treatment enhanced the difference between the two
strains in non-functional ITI responses. The direction of this effect was
interesting, as it was the WKY rats that emitted fewer ITI responses.
Taken together with the pronounced increase in omissions and
decreased accuracy, these data suggest that the overall effect of MP
treatment on the WKY was to reduce their engagement (or alterna-
tively, enhance theirdistractability) in all aspects of thetask. Since their
overall activity remained constant under MP treatment, it suggests that
this loss of engagement was fundamentally the result of a MP-induced
loss of reinforcer efficacy (i.e. motivational rather than motor).
A few significant points to be considered in this study as limitations
and opportunity of further study include the following. First, the rats
weresociallyisolatedforthis study from thestartaswell as restrictedto
20 g of food per day. Sincethese are stressors theresults presented here
between strains couldalsobe relatedto differencesin sensitivity ofeach
strain to such stress. Second, while operant paradigms such as this are
unlikely to invoke anxiety, given the length of pretraining, it is possible
some of the differences in activity and drug sensitivity are the result of
differences in levels of anxiety-like behavior between the two strains.
SHR behaviors possibly related to lower levels of anxiety have been
mostly assessed through open field paradigms that measure the level of
exploration and activity (Howells et al., 2009). The one measure from
our experiment that may be considered an indicator for different levels
of anxiety is the measure of locomotion. However, since the graphs that
depict locomotion for the 2 strains change in parallel (Fig. 4.3),
suggesting that any baseline differences in anxiety-like behavior are
not modulated by thedrug treatment. Third, the rats were treated using
a Latin square design which while having many advantages in that each
animal serves as its own control there is also a limitation that must be
ofvehiclewashout there may havebeen somesensitization takingplace
(even though the MP doses were presented in random order) and SHR
since the WKY rats are themselves a strain derived from a wild-type
progenitor, some limitation exists in the ability to generalize our results
performance deficit of the SHR rats compared with WKY rats at the
attention over the course of the session.
4.4. General discussion
Overall, our findings clearly indicate that the SHR strain, when
evaluated on a task that measures multiple aspects of sustained
operant signal detection performance, show strikingly different
behavior patterns as compared to a background control strain in
both baseline and drug responses. The first theoretical context in
which to consider these findings is one presented by Sagvolden,
Russell and colleagues (e.g. Russell et al., 1995, 2000; Sagvolden and
Sergeant, 1998). These authors argue that hypoactive mesolimbocor-
tical dopamine in the SHR rat models a similar deficit in ADHD, which
is ameliorated by MP treatment. In contrast, in WKY rats, MP, by
P.K. Thanos et al. / Pharmacology, Biochemistry and Behavior 94 (2010) 374–379
producing enhanced synaptic dopamine in meso-striatal dopamine
projections, may have disturbed natural (food) reward related
neurotransmission resulting in the decreased reward sensitivity we
observed. This dissociation provides a parsimonious mediator of this
pronounced dissociation of response.
The second context in which to evaluate these findings is in the
clinical studies have shown that treatment with MP decreases
hyperactivity and impulsivity and improves measures on attention in
adults and children with ADHD (Epstein et al., 2006; McGough et al.,
2005; Prince, 2006; Steinhoff, 2004) and that ADHD patients in general
seem to exhibit a positive linear correlation between symptom
improvement and dose increase (Vitiello et al., 2001), our results are
clearly not consistent with this sort of simple rat to human correspon-
dence view. However, to a large extent, this is a “straw man” in that no
such claim is actually explicitly made in the literature, nor is necessarily
achievable. If viewed in a more limited context, the present data further
potentialcontributionsof a single factor (sensitivity to thereinforcer) in
an operant model, and support the more focused claim that the SHR
of this one factor in ADHD (Sagvolden, 2000).
This work was supported by the NIAAA Intramural Research
Program (AA11034, AA07574, and AA07611), and NIDA/AACAP K 23
Alsop B. Problems with spontaneously hypertensive rats (SHR) as a model of attention-
deficit/hyperactivity disorder (AD/HD). J Neurosci Methods 2007;162(1–2):42–8.
Berger DF, Sagvolden T. Sex differences in operant discrimination behaviour in an animal
model ofattention-deficit hyperactivity disorder. Behav Brain Res1998;94(1):73–82.
Bushnell P. Behavioral approaches to the assessment of attention in animals.
Collins SL, Montano R, Izenwasser S. Nicotine treatment produces persistent increases
in amphetamine-stimulated locomotor activity in periadolescent male but not
female or adult male rats. Brain Res Dev Brain Res 2004;153(2):175–87.
Delini-Stula A, Hunn C. Neophobia in spontaneous hypertensive (SHR) and normoten-
sive control (WKY) rats. Behav Neural Biol 1985;43(2):206–11.
Dell'Anna ME, Luthman J, Lindqvist E, Olson L. Development of monoamine systems
after neonatal anoxia in rats. Brain Res Bull 1993;32(2):159–70.
Diaz-Granados JL, Greene PL, Amsel A. Selective activity enhancement and persistence
in weanling rats after hippocampal X-irradiation in infancy: possible relevance for
ADHD. Behav Neural Biol 1994;61(3):251–9.
operant signal detection task for rats. Behav Brain Res 2005;157:283–90.
Epstein JN, Conners CK, Hervey AS, Tonev ST, Arnold LE, Abikoff HB, et al. Assessing
medication effects in the MTA study using neuropsychological outcomes. J Child
Psychol Psychiatry 2006;47(5):446–56.
Hard E, Carlsson SG, Jern S, Larsson K, Lindh AS, Svensson L. Behavioral reactivity in
spontaneously hypertensive rats. Physiol Behav 1985;35(4):487–92.
Hendley ED, Wessel DJ, Atwater DG, Gellis J, Whitehorn D, Low WC. Age, sex and strain
Holene E, Nafstad I, Skaare JU, Sagvolden T. Behavioural hyperactivity in rats following
postnatal exposure to sub-toxic doses of polychlorinated biphenyl congeners 153
and 126. Behav Brain Res 1998;94(1):213–24.
Howells FM, Bindewald L, Russell VA. Cross-fostering does not alter the neurochemistry
or behavior of spontaneously hypertensive rats. Behav Brain Funct 2009;5(24).
Jones GH, Marsden CA, Robbins TW. Behavioural rigidity and rule-learning deficits
following isolation-rearing in the rat: neurochemical correlates. Behav Brain Res
Kessler RC, Adler L, Barkley R, Biederman J, Conners CK, Demler O, et al. The prevalence
and correlates of adult ADHD in the United States: results from the National
Comorbidity Survey Replication. Am J Psychiatry 2006;163(4):716–23.
Low WC, Whitehorn D, Hendley ED. Genetically related rats with differences
in hippocampal uptake of norepinephrine and maze performance. Brain Res Bull
Mannuzza S, Klein RG, Bessler A, Malloy P, LaPadula M. Adult outcome of hyperactive
boys. Educational achievement, occupational rank, and psychiatric status. Arch Gen
McGough JJ, Biederman J, Wigal SB, Lopez FA, McCracken JT, Spencer T, et al. Long-term
tolerability and effectiveness of once-daily mixed amphetamine salts (Adderall XR)
in children with ADHD. J Am Acad Child Adolesc Psych 2005;44(6):530–8.
Mill J, Sagvolden T, Asherson P. Sequence analysis of Drd2, Drd4, and Dat1 in SHR and
WKY rat strains. Behav Brain Funct 2005;1:24.
Mook DM, Neuringer A. Different effects of amphetamine on reinforced variations
versus repetitions in spontaneously hypertensive rats (SHR). Physiol Behav
Mook DM, Jeffrey J, Neuringer A. Spontaneously hypertensive rats (SHR) readily learn to
vary but not repeat instrumental responses. Behav Neural Biol 1993;59(2):126–35.
Myers MM, Musty RE, Hendley ED. Attenuation of hyperactivity in the spontaneously
hypertensive rat by amphetamine. Behav Neural Biol 1982;34(1):42–54.
Nevin J. A method for the determination of psychophysical functions in the rat. J Exp
Anal Behav 1964;7:169.
NRC Na. Guide for the care and use of laboratory animals. Washington, DC: National
Academy Press; 1996.
Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA. The worldwide prevalence of
Presburger GRJ, Robinson J. Spatial signal detection in rats is differentially disrupted by
Prince JB. Pharmacotherapy of attention-deficit hyperactivity disorder in children and
adolescents: update on new stimulant preparations, atomoxetine, and novel
treatments. Child Adolesc Psychiatr Clin N Am 2006;15(1):13–50.
Puumala T, Ruotsalainen S, Jakala P, Koivisto E, Riekkinen Jr P, Sirvio J. Behavioral and
pharmacological studies on the validation of a new animal model for attention
deficit hyperactivity disorder. Neurobiol Learn Mem 1996;66(2):198–211.
Resnick RJ. Attention deficit hyperactivity disorder in teens and adults: they don't all
outgrow it. J Clin Psychol 2005;61(5):529–33.
Russell V, de Villiers A, Sagvolden T, Lamm M, Taljaard J. Altered dopaminergic function
in the prefrontal cortex, nucleus accumbens and caudate-putamen of an animal
model of attention-deficit hyperactivity disorder—the spontaneously hypertensive
rat. Brain Res 1995;676(2):343–51.
Russell VA, de Villiers AS, Sagvolden T, Lamm MC, Taljaard JJ. Methylphenidate affects
striatal dopamine differently in an animal model for attention-deficit/hyperactivity
disorder—the spontaneously hypertensive rat. Brain Res Bull 2000;53(2):187–92.
Sagvolden T. Behavioral validation of the spontaneously hypertensive rat (SHR) as an
animal model of attention-deficit/hyperactivity disorder (AD/HD). Neurosci
Biobehav Rev 2000;24(1):31–9.
Sagvolden T, Xu T. l-Amphetamine improves poor sustained attention while d-
amphetamine reduces overactivity and impulsiveness as well as improves
sustained attention in an animal model of Attention-Deficit/Hyperactivity Disorder
(ADHD). Behav Brain Funct 2008;23(4):3.
Sagvolden T, Sergeant JA. Attention deficit/hyperactivity disorder—from brain
dysfunctions to behaviour. Behav Brain Res 1998;94(1):1-10.
Sagvolden T, Metzger MA, Schiorbeck HK, Rugland AL, Spinnangr I, Sagvolden G. The
spontaneously hypertensive rat (SHR) as an animal model of childhood
hyperactivity (ADHD): changed reactivity to reinforcers and to psychomotor
stimulants. Behav Neural Biol 1992;58(2):103–12.
Sagvolden T, Pettersen MB, Larsen MC. Spontaneously hypertensive rats (SHR) as a
putative animal model of childhood hyperkinesis: SHR behavior compared to four
other rat strains. Physiol Behav 1993;54(6):1047–55.
Sagvolden T, Russell VA, Aase H, Johansen EB, Farshbaf M. Rodent models of attention-
deficit/hyperactivity disorder. Biol Psychiatry 2005;57(11):1239–47.
Schneider H, Eisenberg D. Who receives a diagnosis of attention-deficit/hyperactivity
disorder in the United States elementary school population? Pediatrics 2006;117(4):
Steinhoff KW. Attention-deficit/hyperactivity disorder: medication treatment-dosing
and duration of action. Am J Manag Care 2004;10(4 Suppl):S99-S106.
Sutterer JR, McSparren J, Ingerman B. Auditory startle in normotensive and
hypertensive rats. Behav Neural Biol 1988;49(3):310–4.
van den Bergh FS, Bloemarts E, Chan JS, Groenink L, Olivier B, Oosting RS. Spontaneously
hypertensive rats do not predict symptoms of attention-deficit hyperactivity
disorder. Pharmacol Biochem Behav 2006;83(3):380–90.
Vitiello B, Severe JB, Greenhill LL, Arnold LE, Abikoff HB, Bukstein OG, et al.
Methylphenidate dosage for children with ADHD over time under controlled
Wilens TE, Biederman J, Spencer TJ. Attention deficit/hyperactivity disorder across the
lifespan. Annu Rev Med 2002;53:113–31.
Wultz B, Sagvolden T, Moser EI, Moser MB. The spontaneously hypertensive rat as an
animal model of attention-deficit hyperactivity disorder: effects of methylpheni-
date on exploratory behavior. Behav Neural Biol 1990;53(1):88-102.
P.K. Thanos et al. / Pharmacology, Biochemistry and Behavior 94 (2010) 374–379