Behavioral Neuroscience 2009, Vol. 123, No.

3, 599 606

2009 American Psychological Association 0735-7044/09/$12.00 DOI: 10.1037/a0015632

Voluntary Physical Exercise Alters Attentional Orienting and Social Behavior in a Rat Model of Attention-Deficit/Hyperactivity Disorder
Michael E. Hopkins, Mita Sharma, Gretchen C. Evans, and David J. Bucci
Dartmouth College
The effects of voluntary physical exercise on attentional function and social behavior were examined in male and female spontaneously hypertensive rats (SHR), a commonly used animal model of attentiondeficit/hyperactivity disorder (ADHD). Rats in the exercise groups had free access to a running wheel for 2 weeks and then all rats received nonreinforced presentations of a visual stimulus (light) during the 1st training session, followed by daily sessions in which the light was paired with food. Nonexercising male and female SHR rats exhibited more unconditioned orienting behavior than WistarKyoto rats. SHRs also exhibited impaired conditioning when the light was paired with food. Exercise reduced orienting in female SHRs but not in male SHRs. In the social interaction task, nonexercising male and female SHRs interacted more with an unfamiliar rat than WistarKyoto rats. Exercise reduced the number of social interactions in female SHRs but not male SHRs. There were no differences in general locomotor activity observed between the nonexercising and exercising SHRs. These data indicate that exercise may preferentially benefit female SHRs, and has implications for using exercise as an intervention for ADHD and for understanding sex differences in the effects of exercise on behavior. Keywords: SHR, associative learning, social interaction, ADHD

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common childhood psychological disorders, affecting 3%7% of children and persisting into adulthood for the majority of those who are diagnosed (American Psychiatric Association, 2000; Mannuzza & Klein, 2000). ADHD is characterized by inattention, impulsiveness, and hyperactivity, which have a variety of cognitive, social, and behavioral consequences (Barkley, 1990, 1991; Barkley, DuPaul, & McMurray, 1990; Biederman, Farone, Keenan, Steingard, & Tsuand, 1991). Current treatments consist mainly of psychostimulants (e.g., methylphenidate), which are thought to exert their effects by increasing both dopaminergic and noradrenergic neurotransmission (Mercugliano, 1999). However, the exact mechanism by which psychostimulants produce improvements in ADHD remains unclear. In addition, some people diagnosed with ADHD do not achieve a therapeutic response to stimulants (Biederman, Spencer, & Wilens, 2004), and the effects of long-term stimulant treatment during childhood are only now being explored (Swanson et al., 2007), with some results suggestive of long-lasting negative effects (Volkow & Insel, 2003). Thus, a significant amount of research on ADHD is currently focused on developing adjunctive or replacement treatments for psychostimulants.
Michael E. Hopkins, Mita Sharma, Gretchen C. Evans, and David J. Bucci, Department of Psychological and Brain Sciences, Dartmouth College. Research funding was provided by National Science Foundation Faculty Early Career Development Award IBN 0441934 and a Dartmouth College Rockefeller Center Research Grant. Correspondence concerning this article should be addressed to David J. Bucci, Department of Psychological and Brain Sciences, Dartmouth College, 6207 Moore Hall, Hanover, NH 03755. E-mail: david.j.bucci@ dartmouth.edu 599

Physical exercise has become increasingly studied for its potential therapeutic effects on mental health. It is well established that exercise improves cognitive function in both humans (Winter et al., 2007) and rodents (Vaynman, Ying, & Gomez-Pinilla, 2004) and has specific effects on neurogenesis and production of trophic factors in the hippocampus and cortex (Molteni, Ying, & GomezPinilla, 2002; van Praag, Christie, Sejnowski, & Gage, 1999). Exercise also has positive effects on depression and anxiety in humans and in rodent models (Binder, Droste, Ohl, & Reul, 2004; Calfas & Taylor, 1994; Stensel, Gorely, & Biddle, in press; Steptoe & Butler, 1996; Strong et al., 2005; Zheng et al., 2006), the effects of which are often comparable to those produced by antidepressant medications (Craft & Landers, 1998; Paluska & Schwenk, 2000). Although very few studies have examined the effects of exercise on persons with ADHD, the existing data suggest that exercise is likely to have similar beneficial effects on behavioral symptoms and cognitive function (Tantillo, Kesick, Hynd, & Dishman, 2002). Moreover, physical exercise has been shown to alter dopamine and norepinephrine transmission (Hattori, Naoi, & Nishino, 1994; Southwick, Vythilingam, & Charney, 2005; Winter et al., 2007), which are thought to be dysfunctional in ADHD (Solanto & Conners, 1982). The present study examined the effects of physical exercise on attentional function and social behavior. We chose to focus on attentional function because of its centrality in current theories on cognitive dysfunction in ADHD (Nigg, 2005; Sergeant, 2005). Impaired social behavior, although not considered a core deficit in ADHD, is often associated with the disorder (Pelham, Fabiano, & Massetti, 2005; Whalen & Henker, 1992) and is notoriously resistant to current interventions (Swanson et al., 2001). Social deficits remain an understudied aspect of ADHD, and the neural mechanisms underlying social impairments remain poorly understood. The study was

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carried out using spontaneously hypertensive rats (SHR), a commonly used rat model of ADHD. The SHR strain shares many of the behavioral and neurobiological characteristics of ADHD, including hyperactivity, impulsivity, inattention, and altered dopaminergic and noradrenergic function (X. Li et al., 2007; Russell, 2002; Russell, Allie, & Wiggins, 2000; Sagvolden, Russell, Aase, Johansen, & Farshbaf, 2005). Several studies with SHR rats have also revealed sex differences in cognitive function that are reminiscent of those observed in ADHD (Berger & Sagvolden, 1998; Bucci, Hopkins, Keene, Sharma, & Orr, 2008; Bucci, Hopkins, Nunez, et al., 2008; Gershon, 2002; Nigg, Blaskey, HuangPollock, & Rappley, 2002); thus, we evaluated the effects of exercise in both male and female SHRs. Exercising SHRs had access to a running wheel in the home cage and were compared with SHRs that did not have access to a running wheel. Nonexercising male and female WistarKyoto (WKY) rats were included as additional control groups. The WKY strain is the most commonly used comparison strain and closest genetic relative of SHRs (Okamoto & Aoki, 1963; Sagvolden et al., 2005). After 2 weeks of exercise, attention and distractibility were assessed by observing orienting responses to a nonreinforced visual stimulus. Orienting is defined as rearing up on the hind legs toward the stimulus (rearing behavior; Holland, 1977, 1984) and is an often-used measure of attentional processing (Gallagher, Graham, & Holland, 1990; Kaye & Pearce, 1984; Lang, Simons, & Balaban, 1997). Rearing behavior rapidly decreases (habituates) when the cue is not followed by reinforcement (unconditioned orienting), reflecting a decrease in attention to a behaviorally irrelevant (and potentially distracting) stimulus (Gallagher et al., 1990; Holland, 1997; Kaye & Pearce, 1984). Social interaction was assessed using a procedure adapted from File and colleagues (File, 1980; File & Seth, 2003). Finally, locomotor activity was measured during the social interaction procedure to provide a task-relevant measure of general activity level.

Apparatus
Running wheel. Rats in the exercise groups had access to an exercise wheel (Med Associates, St. Albans, VT) that was attached to the side of the home cage and accessible through an opening in the wall of the cage. The wheels were 35.6 cm in diameter and consisted of stainless steel rods (4.8 mm in length) spaced 1.6 cm apart. Every quarter revolution of the wheel was recorded by an automatic counter mounted on the side of the apparatus. Associative learning task. The associative learning task was conducted in standard conditioning chambers (24 cm 30.5 cm 29 cm; Med Associates) connected to a computer and enclosed in sound-attenuating chambers (62 cm 56 cm 56 cm) outfitted with an exhaust fan to provide airflow and background noise ( 68 dB). The chambers consisted of aluminum front and back walls, clear acrylic sides and top, and grid floors. A dimly illuminated food cup was recessed in the center of one wall at a height of 5 cm; a 6-W jeweled panel light served as the visual conditioned stimulus and was located 11 cm above the top of the food cup. Mounted 1 cm from the top of the opposite wall was a 6-W bulb that provided background illumination of the chamber. The bulb used for the house light was shrouded on three sides with the open side facing the ceiling of the chamber. Three pairs of photobeam sensors were mounted in the chamber and used to detect rearing behavior. As described previously (Keene & Bucci, 2007), each pair consisted of a transmitter and receiver mounted on the front and back walls of the conditioning chamber. The transmitters emitted a wavelength of 880 nm and the diameter of the canister and aperture of the receivers were 1.9 and 0.3 cm, respectively. The sensors were placed 15 cm above the grid floor and were evenly spaced across the wall of the chamber (8 cm separating the center of a transmitter or receiver to an adjacent one). In that way, a rearing response emitted anywhere in the chamber was detected by one of the sensors (Keene & Bucci, 2007). Snout entries into the food cup were likewise detected by a pair of sensors mounted across the front of the food cup. Surveillance cameras located inside the surrounding shell were also used to videotape the rats behavior. Social interaction task. The social interaction task was conducted in a white plastic tub measuring 119.4 cm 59.7 cm 59.7 cm and located in a small, dimly lit room. A clear Plexiglas cylinder (27.9 cm long 7.6 cm diameter) was located in the center of the tub and used to separate the target rat from the experimental rat during the test session. There were five holes on each side of the cylinder (1.9 cm diameter), two holes on top (1.9 cm diameter), and one hole on either end (3.2 cm and 1.9 cm). A camera was mounted directly above the plastic container and used to videotape the interaction session for subsequent analysis.

Method Subjects
Sixty-nine SHR rats (37 male, 32 female) and 27 WKY rats (14 male, 15 female) were obtained at 8 weeks of age (Harlan SpragueDawley, Indianapolis, IN). Rats were housed in groups of 3 or 4 per cage segregated by sex and strain and maintained on a 14:10 light dark cycle throughout the study. For 7 days, rats were allowed to acclimate to the vivarium and had free access to food and water (Purina standard rat chow: Nestle Purina, St. Louis, MO). Male and female SHRs were then assigned to either exercise groups (SHR-M-E and SHR-F-E, respectively) or nonexercise groups (SHR-M-N and SHR-F-N, respectively). Male and female nonexercising WKY rats served as control groups (WKY-M-N and WKY-F-N). The sample sizes of the groups were as follows: n 19 SHR-M-N, n 18 SHR-M-E, n 16 SHR-F-N, n 16 SHR-F-E, n 9 WKY-M-N, and n 10 WKY-F-N. The remaining 8 WKY rats (4 male, 4 female) were used only as target rats in the social interaction procedure. All procedures were conducted in accordance with Association for Assessment and Accreditation of Laboratory Animal Care guidelines and the Dartmouth College Institutional Animal Care and Use Committee.

Behavioral Procedure
Exercise. Rats in the exercise groups were provided with 24-hr access to a running wheel beginning 2 weeks before the start of the behavioral tasks and continuing throughout the study. The counter that recorded wheel rotations was monitored daily and reset at the same time each afternoon. Associative learning task. Four days after the rats in the exercise groups were provided access to the running wheels, rats in all groups were handled and weighed daily for the next 3 days to establish average baseline body weights. Weights were gradually

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reduced to 85% of baseline over the subsequent 7 days. Once training began, rats were weighed daily and provided enough standard rat chow after the training session to maintain their 85% target weights. Rats were allowed 1 hr to consume the food in individual cages before being returned to the home cage to ensure that each rat ate its ration of food. Water was continuously available in the cages throughout all procedures. On the first day of training, rats were habituated to the conditioning chamber and learned to retrieve food from the food cup during a single 32-min session in which two 45-mg Noyes food pellets were randomly delivered into the food cup 8 times (average intertrial interval [ITI] was 4 min). On the following preconditioning day, rats received 12 nonreinforced presentations of the panel light (10 s each) during the 32-min session (average ITI, 2.75 min). During 8 subsequent daily conditioning sessions, rats received 6 trials consisting of 10-s presentations of the light followed immediately by delivery of two 45-mg food pellets. Social interaction task. Following completion of the associative learning procedure, a subset of rats was provided with free access to food and water for 5 days before participating in the social interaction task (the other rats were used in a separate experiment not described here). The sample sizes of the groups used the social interaction task were SHR-M-N n 16, SHR-M-E n 15, SHR-F-N n 16, SHR-F-E n 15, WKY-M-N n 9, WKY-F-N n 9. At the start of each social interaction session, a target rat (unfamiliar WKY rat of the same sex) was placed in the cylindrical apparatus placed inside the center of the tub (the target rats were previously habituated to the cylinder to minimize stress that may result from being confined). A SHR or WKY rat from each exercising or nonexercising group was then placed in the right-hand corner of the tub. The experimenter left the room and the rat was allowed 10 min to explore the tub. After the session, rats were removed and all surfaces were cleaned with disinfectant.

of scoring the behavior offline rather than during the actual session). Locomotor activity. The videotape of the social interaction session was scored a second time to assess the levels of general locomotor activity in each group of rats. This was important to examine because any group differences that emerged in orienting behavior or social behavior could merely be due to exerciseinduced changes in locomotor activity (e.g., fatigue, etc.). Moreover, comparing activity in SHR and WKY rats allowed us to confirm the reported activity differences between the two strains (Sagvolden et al., 2005). Assessing locomotor activity during the social interaction test, rather than during a separate session in an open field apparatus, for example, provides a direct task-relevant measure of activity. To measure locomotor activity, two straight lines were drawn perpendicular to the long sides of tub on the video screen dividing it into three equal areas, with the middle area containing the cylinder that housed the target rat. An observer blind to condition counted the number of times an experimental rat crossed one of the lines. A line crossing was defined as placing all four paws on the other side of the line.

Data Analysis
Associative learning. Behavior exhibited during presentation of the panel light was analyzed in two separate 5-s periods because orienting behavior has been shown to occur primarily during the first half of a 10-s presentation of a visual stimulus, and food cup behavior occurs primarily during the second half of the conditioned stimulus in appetitive conditioning preparations (Holland, 1977). For the unconditioned orienting analysis, the number of breaks in the three photobeams used to detect rearing behavior was summed for each trial. Previous studies indicate that it is unlikely that a rearing response would simultaneously break more than one of the three photobeams (Keene & Bucci, 2007). The data were then combined into two blocks averaged across Trials 1 6 and Trials 712 to assess habituation of the unconditioned orienting response (Gallagher et al., 1990). A repeated measures analysis of variance (ANOVA) was used to assess group differences in rearing using block as the within-subjects variable and group as the between-subjects variable (SHR-E, SHR-N, WKY-N). Separate analyses were conducted for males and females because our planned comparisons were focused on within-sex strain and exercise differences. During the conditioning sessions, the number of breaks in the beam placed across the front of the food cup were counted and averaged across the trials in each session. Group differences were analyzed using an ANOVA with group as the between-subjects variable and session as the within-subjects variable. Significant differences were subsequently analyzed using Fishers PLSD test. Social interaction and locomotor activity. The number of interactions or line crossings were analyzed using a one-way ANOVA with group as the between-subjects variable. Significant differences were subsequently analyzed using Fishers PLSD test. All statistical analyses were conducted using an alpha level of .05.

Behavioral Observations
Associative learning task. On the preconditioning day, breaks in the three photobeams mounted on the walls of the chamber were monitored by the computer and used to measure unconditioned orienting behavior. Orienting was defined as rearing on the hind legs with both forepaws off the ground (Holland, 1977). Grooming was not considered an instance of rearing even if both forepaws were off the ground. During the conditioned sessions, breaks in the photobeam located across the entry of the food cup were monitored by the computer and used as a measure of conditioned responding. Social interaction task. Social behavior was assessed using videotapes of the interaction sessions. The primary measure of social interaction was the number of times the experimental rat approached and sniffed inside one of the holes in the cylinder that contained the target rat. In addition, walking around the cylinder with continuous sniffing was counted as an interaction. Exploration of other parts of the cylinder (i.e., areas without holes) was not counted as an interaction. Interactions initiated by the unfamiliar WKY rats when they poked their noses out of the front hole were not scored unless the experimental rat reciprocated the interaction. Behavioral observations were conducted by an observer who was blind to the identity of the experimental rats (hence the importance

Results Exercise
The average number of daily wheel rotations was 23,723 per cage of 4 female SHR rats and 20,837 per cage of 4 male SHR rats.

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Because 4 rats shared each wheel, it was not possible to know the exact distance each rat ran, precluding statistical analysis. However, other studies have revealed that group-housed rodents spend approximately equal amounts of time on the wheel when it is freely accessible as in the present study (Fox, Hammack, & Falls, 2008).

Associative Learning
Unconditioned orienting behavior. The amount of unconditioned orienting behavior observed during nonreinforced presentations of the light is shown in Figure 1. The three groups of female rats (Figure 1A) and the three groups of male rats (Figure 1B) all exhibited habituation of the orienting response from the first block of trials to the second block of trials. This was confirmed by a repeated measures ANOVA, which revealed a significant main effect of block for both females, F(1, 39) 24.9, p .0001, and males, F(1, 42) 24.0, p .0001. There was also a significant main effect of group for both females, F(2, 39) 17.6, p .0001, and males, F(2, 43) 6.4, p .004. Post hoc analyses revealed that the nonexercising female SHR group reared more than the female WKY group ( p .0001), consistent with the notion that SHRs are hyper-responsive to environmental stimuli. Female SHRs that exercised reared significantly less than the nonexercising SHR females ( p .0003), but significantly more than WKY

females ( p .004). By comparison, both groups of male SHRs reared more than male WKY rats ( ps .001), but exercise did not produce a significant effect on unconditioned orienting behavior in male SHRs ( p .7). The Block Group interaction was not statistically significant for either females or males ( ps .1). Conditioned food cup behavior. When the light was subsequently paired with food reward, rats in all groups exhibited increased food cup behavior during presentation of the light as training progressed (Figures 2A and 2B). This was confirmed by a repeated measures ANOVA, which revealed a significant main effect of session for both females and males, F(7, 273) 63.3, p .0001, and F(7, 301) 49.8, p .0001, respectively. There was also a significant main effect of group for the female rats, F(2, 39) 3.8, p .03, and a significant Group Session interaction, F(14, 273) 2.7, p .001. Post hoc analyses indicated that female WKY rats exhibited more conditioned food cup behavior than either of the two female SHR groups ( ps .002). The two SHR groups were not significantly different from each other ( p .5). Similarly, there was significant main effect of group for male rats, F(2, 43) 3.9, p .03. WKY males exhibited more food cup behavior than either group of male SHRs ( ps .0003), whereas the two male SHR groups did not differ from each other ( p .4). The Group Session interaction was not statistically significant for the male rats ( p .5).

Social Interaction
The number of interactions exhibited by male and female rats is illustrated in Figure 3. A one-way ANOVA revealed a main effect of group for both females, F(2, 37) 3.8, p .03, and males, F(2, 37) 16.3, p .001. Post hoc analyses indicated that nonexercising female SHRs interacted more than either nonexercising female WKY rats or exercising female SHRs ( ps .05). The female WKY group and the exercising female SHR group did not differ from each other ( p .9). A different pattern of results was observed for the male rats. Both groups of male SHRs interacted more than the male WKY rats ( ps .001). Moreover, there was no significant difference between the exercising male SHRs and the nonexercising male SHRs ( p .1).

Locomotor Activity
The amount of locomotor activity exhibited during the social interaction procedure is shown in Figure 4. Consistent with the hyperactive phenotype of SHR rats, females in both the exercising and nonexercising SHR groups exhibited more locomotor activity than the female WKY group ( ps .001). An important finding was that locomotor activity did not differ between the two female SHR groups ( p .9). Similarly, both male SHR groups crossed more lines than the male WKY rats ( ps .01), whereas there was no significant difference between the two male SHR groups ( p .1).

Figure 1. Unconditioned orienting (rearing behavior) observed during repeated presentation of a nonreinforced visual stimulus. The number of breaks in the photobeams used to detect rearing behavior are shown on the y-axis. Blocks of trials (first 6 and second 6) are shown on the x-axis. Data are means standard error. SHR-M-E spontaneously hypertensive exercising male rats; SHR-F-E spontaneously hypertensive exercising female rats; SHR-M-N spontaneously hypertensive nonexercising male rats; SHR-F-N spontaneously hypertensive nonexercising female rats; WKY-M-N WistarKyoto nonexercising male rats; WKY-F-N WistarKyoto nonexercising female rats.

Discussion
The present study examined the effects of voluntary physical exercise on attentional orienting and social behavior in male and female SHR rats. Regardless of sex, the SHR groups exhibited more orienting behavior during presentation of a nonreinforced visual stimulus than nonexercising WKY control rats. These data

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Figure 2. Conditioned food cup behavior during training sessions in which the light was paired with food reward. The number of nose pokes into the recessed food cup is noted on the y-axis. Data are means standard error. SHR-M-E spontaneously hypertensive exercising male rats; SHR-F-E spontaneously hypertensive exercising female rats; SHRM-N spontaneously hypertensive nonexercising male rats; SHR-F-N spontaneously hypertensive nonexercising female rats; WKY-M-N WistarKyoto nonexercising male rats; WKY-F-N WistarKyoto nonexercising female rats.

Figure 3. Social interaction between spontaneously hypertensive rats and WistarKyoto rats in the exercise and nonexercise groups and an unfamiliar WistarKyoto rat. The number of social interactions reflects the number of contacts made by an experimental rat with holes in the cylinder containing the target rat during a 10-min session. Data are means standard error. SHR-M-E spontaneously hypertensive exercising male rats; SHRF-E spontaneously hypertensive exercising female rats; SHR-M-N spontaneously hypertensive nonexercising male rats; SHR-F-N spontaneously hypertensive nonexercising female rats; WKY-M-N Wistar Kyoto nonexercising male rats; WKY-F-N WistarKyoto nonexercising female rats.

are consistent with previous studies indicating that SHRs are hyper-responsive and prone to distraction by irrelevant environmental stimuli (Sagvolden et al., 2005). Exercise reduced the amount of orienting exhibited by female SHR rats to a level that was between that of the nonexercising female SHRs and WKYs. However, a different pattern of results was observed in the male groups in that the amount of orienting behavior was comparable in the exercising male SHRs and nonexercising male SHRs. One interpretation of these data is that exercise was effective in reducing nonreinforced orienting responses to the light in female SHRs but not in male SHRs. This interpretation is consistent with findings in humans suggesting that women may derive more cognitive benefit from physical exercise than men (Colcombe & Kramer, 2003). However, a comparison between Figures 1A and 1B reveals that nonexercising female SHRs reared more than nonexercising male SHRs. This was supported by a follow-up statistical analysis comparing mean levels of orienting in male and female nonexercising SHRs, t(33) 3.04, p .005. Thus, it may be that the 2-week exercise regimen used in this study was sufficient to reduce orienting behavior only to a certain extent, and that the data reflect a floor effect in males. Regardless, the hyperresponsivity of female SHRs to a behaviorally irrelevant stimulus is consistent with a growing literature regarding potential sex difference in persons with ADHD. Indeed, a number of studies indicate that girls diagnosed with ADHD may be more cognitively impaired than boys with ADHD (Gershon, 2002; Nigg et al., 2002; Spencer, Biederman, & Mick, 2007). Although boys are more often diagnosed with ADHD than girls (ranging from 2:1 to 5:1; Gaub & Carlson, 1997; Wolraich, Han-

nah, Pinnock, Baumgaertel, & Brown, 1996), the high prevalence rate for ADHD indicates that a significant number of girls are diagnosed with the disorder. Yet, girls remain a largely understudied population of persons affected by ADHD (Gershon, 2002). Establishing animal models of sex differences in ADHD-like behavior may provide a means to study the biological basis of sex differences in this disorder (Bucci, Hopkins, Keene, et al., 2008; Bucci, Hopkins, Nunez, et al., 2008). Indeed, several studies have now found sex differences in SHR rats. For example, in an operant discrimination task, male SHRs exhibited shorter delay-ofreinforcement gradients, whereas female SHRs exhibited deficits more consistent with inattention (Berger & Sagvolden, 1998; Sagvolden & Berger, 1996). Female SHRs also exhibit deficits in

Figure 4. Locomotor activity in spontaneously hypertensive rats and WistarKyoto rats during the 10-min social interaction session. Data reflect the number of times rats in each group crossed one of two lines that separated the social interaction apparatus into thirds (M SE). SHR-ME spontaneously hypertensive exercising male rats; SHR-F-E spontaneously hypertensive exercising female rats; SHR-M-N spontaneously hypertensive nonexercising male rats; SHR-F-N spontaneously hypertensive nonexercising female rats; WKY-M-N WistarKyoto nonexercising male rats; WKY-F-N WistarKyoto nonexercising female rats.

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inhibitory behavior compared with males (Bucci, Hopkins, Keene, et al., 2008). When the light was later paired with food reward during the associative learning task, WKY rats acquired the conditioned food cup response more quickly than either exercising or nonexercising SHR rats, regardless of sex. These data provide additional evidence of learning-related impairments in SHR rats (Bucci, Hopkins, Nunez, et al., 2008) that are also consistent with cognitive deficits observed in persons with ADHD (Fischer, Barkley, Smallish, & Fletcher, 2005). Moreover, the enhanced rates of conditioning in WKY rats compared with SHR rats suggest that the lower amounts of unconditioned orienting observed in WKY rats compared with SHRs were not attributable to general hyporesponsiveness in the WKY strain. During the social interaction test, both male and female nonexercising SHRs exhibited hyper-social behavior in that they interacted more with an unfamiliar WKY target rat than did the male and female WKY rats. It is unlikely that increased interaction observed in SHRs was simply caused by exposing them to a rat of a different strain. Indeed, previous studies indicate just the opposite: SHR rats interact less when paired with a non-SHR rat than another SHR (Ferguson & Cada, 2004). Exercise reduced the number of social interactions in female SHRs to the level observed in the WKY rats. In contrast, male SHRs that exercised interacted just as much as nonexercising SHR males. The sex difference in how exercise affected the amount of social interactions cannot be explained by a floor effect in males, as observed in the orienting data. Indeed, both male and female nonexercising SHRs exhibited similarly high levels of interaction (see Figure 3). These data suggest that hyper-social behavior in SHR males may be less sensitive to the effects of exercise compared with females and has implications for the potential use of exercise as an adjunctive treatment for ADHD. Indeed, it may be that the effect size is smaller in males compared with females, resulting in a statistically nonsignificant difference between the exercising and nonexercising males SHRs ( p .1). Moreover, future studies should address whether additional exercise would produce effects in males that are more comparable to those observed in female SHRs. An important finding is that exercise did not have an effect on general locomotor activity in either male or female SHR rats. Both groups of female SHR rats were more active than female WKYs and both groups of male SHRs were more active than male WKYs. These data make it unlikely that the decreases in orienting behavior and social behavior exhibited by exercising SHR rats were simply due to fatigue or hypoactivity. Moreover, the increased locomotor activity observed in the SHR groups is consistent with many previous studies that have documented hyperactivity in SHRs compared with WKY rats (Sagvolden et al., 2005). To our knowledge, these data are among the first to establish that SHR rats exhibit alterations in social behavior reminiscent of those observed in ADHD. One other study examined social behavior in SHRs and likewise found an increase in social interaction compared with Wistar rats (Goto, Conceicao, Ribeiro, & Frussa Filho, 1993). Although not considered a core deficit in ADHD, altered social behavior is often associated with the disorder and dramatically affects interpersonal relationships and communication, resulting in negative peer relationships and social ostracism (Whalen & Henker, 1992). Indeed, although the specific constellation of symptoms arising from ADHD may vary considerably

among individuals, the social and academic problems resulting from the disorder are less varied and often have the greatest impact on those who suffer from ADHD (Pelham et al., 2005). Identifying novel methods of alleviating impaired social functioning is of particular interest because of its resistance to current interventions, even when other outcomes have shown marked improvement (Swanson et al., 2001). The SHR strain exhibits abnormalities in dopaminergic and noradrenergic function that parallel those observed in persons with ADHD (X. Li et al., 2007; Sagvolden et al., 2005). Because physical exercise can alter dopaminergic systems (Hattori et al., 1994), future studies might investigate whether the behavioral changes reported here are due to changes in dopaminergic neurotransmission. However, it is also possible that exercise may exert its behavioral effects by modulating the function of the cerebellum. Indeed, there has been increasing interest in the role of the cerebellum in the pathogenesis of ADHD. Structural anomalies of the cerebellum are among the most consistently reported features of ADHD (Mackie et al., 2007; Mostofsky, Reiss, Lockhart, & Denckla, 1998). Cerebellar abnormalities and impairments in cerebellar-dependent behavior have also been found in the SHR strain (Chess & Green, 2008; Q. Li et al., 2007; Shigematsu, Niwa, & Saavedra, 1986). It is interesting that decreased cerebellar volume has been associated with psychosocial impairment (Wassink, Andreasen, Nopoulos, & Flaum, 1999) and difficulty understanding social cues (Schmahmann & Sherman, 1998). Moreover, exercise has been shown to improve blood flow and reorganize neural representations in the cerebellum (Holschneider, Yang, Guo, & Maarek, 2007; Isaacs, Anderson, Alcantara, Black, & Greenough, 1992). This suggests that changes in social behavior observed in female SHRs following exercise may have been mediated through functional changes in the cerebellum. Symptoms of hyperactivity and impulsivity remit much more abruptly than inattention during development (Spencer et al., 2007), and children, adolescents, and adults with the inattentive subtype (20%30%) of ADHD are more likely to be female compared with those diagnosed with the hyperactivity/impulsivity subtype ( 15%; Spencer et al., 2007). Taken together, these findings are consistent with the notion that the female phenotype of ADHD is particularly vulnerable to deficits that persist into adulthood. Thus, identifying new treatment regimens, such as physical exercise, may be particularly important for this group of persons diagnosed with ADHD. The notion that females with ADHD may reap greater benefits from exercise than males is supported by the specific benefits that are known to result from physical exercise. That is, exercise has clear cognitive benefits (Vaynman et al., 2004; Winter et al., 2007) and protects against stress-related mood disorders such as anxiety and depression (Greenwood et al., 2003; Greenwood, Foley, Burhans, Maier, & Fleshner, 2005; Salmon, 2001). Females who are diagnosed with ADHD tend to be more impaired on cognitive tasks and are at higher risk for developing depression and anxiety (Biederman et al., 2008; Gershon, 2002). In addition, PET studies have revealed reduced global metabolism in ADHD, and this effect appears to be more specific to females than males with the disorder (Ernst et al., 1994; Zametkin et al., 1993), providing further evidence that physical exercise, which increases global metabolic function, may preferentially benefit females with ADHD.

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Received October 24, 2008 Revision received February 10, 2009 Accepted February 14, 2009