Attention-deficit/hyperactivity disorder (ADD/ADHD) has been emerging as a world-wide psychiatric disorder. There appears to be an increasing rate of stimulant drug abuse, specifically methylphenidate (MPH) which is the most common treatment for ADHD, among individuals who do not meet the criteria for ADHD and particularly for cognitive enhancement among university students. However, the long term effects of exposure to MPH are unknown. Thus, in light of a developmental approach in humans, we aimed to test the effects of adolescence exposure to enriched environment (EE) followed by MPH administration during early adulthood, on reactions to stress in adulthood. Specifically, at approximate adolescence [post natal days (PND) 30–60] rats were reared in EE and were treated with MPH during early adulthood (PND 60–90). Adult (PND 90–92) rats were exposed to mild stress and starting at PND 110, the behavioral and endocrine effects of the combined drug and environmental conditions were assessed. Following adolescence EE, long term exposure to MPH led to decreased locomotor activity and increased sucrose preference. EE had a beneficial effect on PPI (attentive abilities), which was impaired by long term exposure to MPH. Finally, the interaction between EE and, exposure to MPH led to long-term elevated corticosterone and testosterone levels. In view of the marked increase in MPH consumption over the past decade, vigilance is crucial in order to prevent potential drug abuse and its long term detrimental consequences.
Citation: Avital A, Dolev T, Aga-Mizrachi S, Zubedat S (2011) Environmental Enrichment Preceding Early Adulthood Methylphenidate Treatment Leads to Long Term Increase of Corticosterone and Testosterone in the Rat. PLoS ONE 6(7): e22059. https://doi.org/10.1371/journal.pone.0022059
Editor: Thomas Burne, University of Queensland, Australia
Received: April 10, 2011; Accepted: June 13, 2011; Published: July 15, 2011
Copyright: © 2011 Avital et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors have no support or funding to report.
Competing interests: The authors have declared that no competing interests exist.
Methylphenidate (MPH; Ritalin) is commonly prescribed for the treatment of attention-deficit/hyperactivity disorder (ADD/ADHD), a psychiatric disorder that is more common during childhood and early adulthood. Treatment with MPH is generally effective in reducing symptoms associated with ADHD: inattentiveness, impulsivity, impaired working memory and hyperactivity –. Despite the widely recognized efficacy of MPH in the treatment of ADHD, little is known about the neural mechanisms that underlie the behavioral/cognitive actions of this drug. MPH inhibits dopamine and norepinephrine transporters, thereby increasing the extra-cellular concentration of these neurotransmitters –.
Although ADHD can be difficult to diagnose , , the use of prescription stimulants for its treatment has increased over the past decade –, particularly of MPH –. The latter findings may increase the likelihood that individuals who do not meet ADHD criteria, are being exposed to stimulants ,  and could lead to extensive MPH abuse. The documented abuse consists of 6–9% non-medical consumption by individuals who do not have ADHD , , and 14% secondary abuse by ADHD patients who use their prescriptions for over consumption . Importantly, MPH is also being widely consumed in an unsupervised manner for improving concentration and enhancing performance, or for recreational purposes among university students –. A report from 2006 indicates that more than 7 million people in the US have abused ADHD stimulants, and as many as 750,000 teenagers and young adults may show signs of addiction . Yet, little is known about the long-term consequences of the exposure to MPH.
In trying to assess the time frame of adolescence in rat, it is difficult to characterize absolute boundaries . Spear L.P. (2000) suggested that adolescence be considered between postnatal day (PND) 28–42  while Spear L. (2000) suggested PND 28–55 . Laviola (2003) suggested a wider definition between PND 21–60 , and recently Marco (2011) suggested PND 35–50 . Thus, in order to encompass the various definitions, in the current study we have defined PND 30–60 as adolescence. Previous studies, utilizing a rat model, showed that the exposure to MPH during PND 20–35 decreased response to rewarding stimuli, increased depressive- and anxiety-like behaviors and enhanced corticosterone levels following restraint stress in adulthood –. However, in order to increase face validity of an animal model of MPH treatment in a non-ADD/ADHD condition, we aim to examine the long-term behavioral consequences of administration of MPH during early adulthood. Therefore, we postulate that a common human developmental path is comprised of the exposure to enriched environment (EE) during adolescence, a long term use/abuse of MPH during early adulthood, followed by coping with a stressful experience in adulthood. Importantly, we have focused on MPH treatment that occurred during early adulthood, since MPH has been widely unruly used by students for cognitive enhancement, weight loss or euphoric effects , , .
Materials and Methods
Male Wistar rats were purchased from Harlan (Jerusalem, Israel) and were reared at the institutional animal housing facility. Rats were housed four per cage (30L×30W×18H cm). Room temperature maintained at 23±1°C with 67% humidity with a 12∶12 day/night cycle (lights on at 06:00) and ad-libitum food and water access allowed. All behavioral tests and manipulations were held between 07:00 and 17:00. This study was carried out in strict accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Israel Ministry of Health (Permit Number: IL-09-06-040). All efforts were made to minimize animal suffering.
Between PND 30–60 (adolescence) rats were kept under enriched environment (EE) conditions. During early adulthood (between PND 60–90) rats were treated with MPH. Finally, in order to examine ability to cope with mild stress in adulthood, rats were exposed to stress (acute swim, elevated platform and restraint) during three consecutive days (PND 90–92) (Figure 1). To evaluate the long-term behavioral consequences, starting at PND 110, all rats went through behavioral tests (i.e; open field, sucrose preference test and pre-pulse inhibition). Rats were decapitated twenty-four hours after the behavioral tests and trunk blood samples were collected for hormonal analysis (Figure 1).
Between PND30 and 60, forty rats were kept under enriched environment conditions, 8 rats interacted socially per customized cage (80L×50W×50H cm) with various objects (e.g. running wheel, stairs, tubes, Lego cubes, wood parts, hanging items, etc.). Each week the objects were replaced with new ones for subtle novelty. The cage also contained an extra elevated (25 cm) surface (20L×50W cm) that was accessible via stairs. In addition, a sandbox (20L×10W cm) was included in the main floor; in order to provide textural diversity within the cage.
Methylphenidate hydrochloride (Sigma-Aldrich, St. Louis, USA) was dissolved in a sterile saline solution. Rats were injected with methylphenidate hydrochloride (randomly 4 days per week/2.7 mg/Kg body weight/intraperitoneally) or with saline, between PND 60–90.
Rats were exposed to the following stressors during 3 consecutive days (PND 90–92).
At PND 91, rats were placed on a 50 cm high, 10 cm diameter platform three times for 30 minutes each time with 1 hour spent in a resting cage between periods on the platform .
At PND 92, rats were placed in a radial-shaped restrainer (6 cm height) according to the exposure regime of the elevated platform (modified from ).
All tests were carried out in a dimly lit room (50 lux) with stable temperature 24±1°C.
Open Field Test.
The open field is made of a black lusterless Perspex box (100L×100W×40H cm). Rats were placed in the corner of the open field (facing the wall). Their behavior (i.e; locomotor activity and freezing) was videotaped for 5 min by a CC TV Panasonic camera with post-recording analysis performed using Ethovision XT software (Noldus, Wageningen, The Netherlands).
Pre-Pulse Inhibition (PPI).
The PPI test is held in a ventilated sound proof box (Campden instruments, UK) and aims to examine the function of the sensorimotor gating. The session (a total of 80 trials) started with 3 min acclimatization period with a 57 dB background noise level that was delivered continuously throughout the test session. To evaluate the startle response, the first and last ten trials consisted of single 40 ms, 120 dB “pulse-alone” startle stimuli. These trials were used to obtain a measure of habituation in response to repeated delivery of the startling stimuli (inter-trial-interval 1 min). The middle 60 trials were comprised of random delivery of ten “no stimuli” trials, during which no stimuli are delivered, ten “pre stimuli” (at 59, 61, 65, 69, 73, 78 or 85 dB), and forty “pre pulse” trials. The latter trials, consisted of a single 120 dB pulse preceded (80 ms interval) by a 20 ms “pre pulse” of 2, 4, 8, 12, 16, 21 or 28 dB above background (i.e., 59, 61, 65, 69, 73, 78 or 85 dB). Finally, PPI was calculated as a percent score that reflects the ratio between the inhibited (“pre pulse” trial) response, and the individual startle (“pulse-alone”) response: [100−(max response to “pre pulse” trial/max response to “pulse alone” trial×100)].
Sucrose Preference Test.
During the acclimatization period (1 week), rats were allowed to consume 1% (w/v) sucrose or tap water, in order to overcome neophobia. Moreover, they were under water limitation (access allowed for 4 h a day). On the 6th day the amount of total liquid consumption was assessed (over a period of 4 h), to detect general differences in liquid consumption. Following acclimatization period, on the 8th day, the test was carried out individually for each rat: following a 16 h period of water limitation, two drinking bottles, identical to the home cage water bottles, were inserted into the cage through the metal mesh top cover. The bottles, one containing a 10% sucrose solution and the other water, were weighed just before the test and immediately following its completion (after 4 h) and the sucrose preference which indicates natural reward was calculated. The relative positioning of the bottles providing sucrose and water was reversed after two hours, in order to prevent the development of side preference.
Corticosterone and Testosterone
Twenty-four hours after the behavioral tests, rats were decapitated. To avoid circadian variability, all decapitations were performed between 11–12 a.m., when plasma hormones concentration is relatively low. Blood samples were centrifuged (2000×g at 4°C for 20 min), serum was collected and stored at −80°C until assayed. Serum corticosterone and testosterone levels were assessed using commercial ELISA kits (AssayPro, St. Charles, MO, USA) according to the manufacturer's instructions.
Data were analyzed for statistical significance using two-way ANOVA with group and treatment as main factors (4×2). For analyzing body-weight and PPI we used ANOVA for mixed design, with group as between subject's factor and test timing or pre-pulse intensity as within subject's factor. In order to further explore the main effects, a Post-Hoc Tukey test was performed. A result was significant when p<0.05. All tests were calculated as two-tailed with SPSS V17.0. Results are presented as means ± standard error of the means (SEM).
The long-lasting effects of MPH on locomotion and freezing behaviors
A significant difference in locomotor activity measured by distance (Figure 2A) and velocity (Figure 2B) was detected between the groups [F(3, 71) = 25.4, P<0.0001)]. We found that adolescence EE led to a long term decrease in distance and velocity (P<0.0001). Surprisingly, MPH administration following adolescence EE intensifies these effects over time (P<0.022; P<0.008, respectively). Interestingly, the exposure to a brief stress (EE+Stress) in adulthood moderates these alterations. In order to exclude the effect of body weight on locomotor behavior, indeed an insignificant difference in body weight gain (Figure 2C) between all groups was found [F(7, 71)<1].
A significant difference in distance (A) and velocity (B) were detected between the groups in the open field test. Rats exposed to MPH following EE showed the lowest distance and velocity. These effects were not related to differences in body weight (C). MPH treatment significantly increased freezing duration (D) compared to saline. Following EE, MPH led to the highest freezing duration. * P<0.0001 versus control; ** a: P<0.022, b: P<0.008, c: P<0.0001 versus EE saline; n = 9 to 10 per group.
Measuring freezing behavior (Figure 2D), a significant difference was detected between the groups [F(3, 71) = 75.83, P<0.0001]. The highest freezing level was detected in the EE group (P<0.0001), while the EE followed by stress (EES) demonstrated a significant increase compared to both control and stress groups (P<0.0001). In addition, MPH was associated with significantly higher freezing in both control (P<0.001), EE (P<0.0001) and EES (P<0.006) groups.
MPH modulates the response to rewarding stimulus (hedonia)
In order to test the response to rewarding stimulus, we have tested hedonia/anhedonia rate by measuring sucrose intake (Figure 3). A significant diversity in sucrose preference was observed between the groups [F(3, 71) = 31.57, P<0.0001]. Complementarily to the highest freezing level observed in the EE group, a significant long term anhedonia was detected (P<0.019). Fascinatingly, MPH administration has led to anhedonia in the controls (P<0.001), while in the EE group MPH significantly shifted to increased hedonia (P<0.0001). Finally, the EES group showed a significant hedonia (P<0.0001) as compared with either the EE or stress groups, that was not affected by MPH administration.
Considerable variation in sucrose intake was observed between the groups. While significant long term anhedonia was detected in the EE group, MPH treatment following EE significantly recovers this effect. * P<0.019 versus control; ** P<0.0001 versus EE saline; n = 9 to 10 per group.
MPH detrimental effects on Pre-Pulse Inhibition following adolescence EE or preceding stress in adulthood
Pre-Pulse Inhibition test (PPI) is a neurological phenomenon (measured also in human subjects) in which a weaker acoustic pre-pulse, inhibits the reaction to a subsequent strong startling pulse. The reduction of the amplitude of response reflects the ability of the nervous system to temporarily adapt to a strong sensory stimulus when a preceding weaker signal is given. We found (Figure 4) a significant distinction in PPI along different pre- intensities (59 db to 85 db) across all groups [F(6, 30) = 459.42, P<0.0001) and between the groups [F(3, 35) = 161.12, P<0.0001]. The exposure to adolescence EE has led to a long term beneficial effect on PPI (P<0.0001), while stress following EE has lessened this increase (P<0.019). When administrated following EE (EE+MPH) or prior to stress (MPH+stress), MPH had a long term deteriorating effect on PPI (P<0.022; P<0.004, respectively). However, by itself (MPH group) or in the EES group, MPH seemed to have only minor effect.
Significant differences in PPI scores were observed. EE led to the highest PPI compared with all groups (P<0.0001). Following MPH treatment, the EES group showed higher PPI compared with control (P<0.0001) and stress (P<0.001) groups. A panel of representative traces demonstrate the differences in maximal response inhibition (at pre-intensity of 69 dB) of all four groups, with and without MPH. n = 9 to 10 per group.
MPH leads to a long-term increase of Corticosterone and Testosterone depending on the developmental context
In trying to depict the endocrine mechanism mediating the effects of MPH in the context of the developmental approach, previous studies found that EE lowered baseline corticosterone (CORT) level  or did not influence its level at all , while MPH (similar to hyper-arousal following stress) was found to increase CORT level , , , . To clarify the aforementioned behavioral effects, we measured serum CORT level (Figure 5A) and found a significant difference between the groups [F(3, 56) = 51.019, P<0.0001]. Without MPH, a long term significant CORT reduction was found in the EE group (P<0.026) while in the stress and the EES groups CORT was elevated (P<0.004). Interestingly, MPH administration increased CORT level (more than 152%) in the EE (P<0.0001) and EES (P<0.002) groups.
A significant difference in CORT (A) and TST (B) levels was observed. MPH treatment significantly increased CORT level in the EE and EES groups (* P<0.0001; ** P<0.002 compared with their respective controls). TST level was similar across all groups, while MPH treatment increased TST level in both EE and EES groups (* P<0.001; ** P<0.012 compared with their counterpart controls). n = 9 to 10 per group.
Finally, MPH is known to affect aggression , . Specifically, it has been suggested that children with ADHD generate more aggressive responses to provocation and that this may be exacerbated by administration of MPH . This led us to examine the endocrine correlate of aggression, by measuring Testosterone (TST) serum level –. A significant variation in TST level (Figure 5B) was observed between the groups [F(3, 56) = 14.12, P<0.0001]. Surprisingly, we found a robust long-term increase (more than 154%) in the EE and EES groups treated with MPH (P<0.001 and P<0.012 respectively).
Psychostimulants have proven to be an effective pharmacotherapy for ADD/ADHD, with MPH being the preferred medication for this neuropsychiatric disorder . Moreover, in several pediatric populations more than half of those treated with MPH do not meet the criteria for attention disorders , , .Given the prevalence of prescribed use of MPH, it is surprising that only few studies have utilized a developmental approach to explore the long-term effects of MPH. These studies showed enduring behavioral alterations in adult animals as a consequence of repeated therapeutic dose of MPH exposure during their juvenile period –. However, in order to increase face-validity, one should take into consideration the importance of timing and the diversity of life experiences. The latter has major importance in light of the raise of MPH abuse among college students , , . Thus, we aim to examine the long-lasting behavioral and endocrine consequences of the exposure to environmental enrichment (during adolescence), long term MPH treatment (during early adulthood) and stress (during adulthood).
Our findings show no significant effect of MPH administration on body weight, similar to ADHD children treated with MPH . However, we found that adolescence EE lead to a long term decrease in locomotor activity, while MPH increased these effects. In line with these findings, we also found that EE increased freezing duration compared with control group. It should be noted that MPH increased freezing in both control and EE groups. To this end, Bolanos et al (2003) found that pre-pubertal MPH treatment also decreased locomotor activity . Moreover, Britton et al (2007) found enhanced anxiety-like behaviors in adult rats caused by early developmental MPH treatment .
However, in our study we suggested to take into account also the environmental context in which the individual grows, since we postulate that many children that were raised under EE consume MPH mainly during early adulthood. In support of this idea, while some reports indicate that EE has an anxiolytic effect , , , others report that the exposure to EE pre-pubertally may serve as anxiogenic factor , . A wide range of data in the literature suggests that EE has beneficial effects on various behavioral parameters in rodents. However, the magnitude of these effects and their persistence after the cessation of enrichment vary markedly across studies according to the developmental stage in which the exposure occurred (starting pre-weaning  up to old age ) and to the duration of enrichment (from a couple of weeks ,  to up to a year ) .
In addition, EE has been suggested to recover some of the deteriorating effects of early exposure to stress –; however the preceding effects of EE on the reaction to stress later in life are less investigated. In support of our findings, Amaral et al (2008) also found that 4 weeks of EE post weaning decreased locomotion activity in the open field test .
Since it was documented that MPH treatment during pre-adolescence often produces side effects such as decreased response to rewarding stimuli (i.e; increased depressive-like behaviors) , , , we have measured anhedonia utilizing the sucrose preference test. Similar to the aforementioned findings, we also found that MPH led to anhedonia in control animals. However, the exposure to MPH following adolescence EE, has recovered the anhedonia observed to the controls level. Interestingly, the combination of adolescence EE and stress in adulthood, both in MPH-treated and -untreated animals, led to increased hedonia. Complementarily, EE+MPH (with or without stress) led to the highest hedonia level, i.e; the preference of the rewarding stimulus.
Since treatment with MPH is generally effective in reducing such symptoms associated with ADHD as inattentiveness  and it also has been found that EE improved attentive abilities , , we examined in our non-ADHD rats the attention ability as reflected by the PPI test. Prepulse inhibition (PPI) of the acoustic startle reflex refers to the reduction in the magnitude of the startle reflex when a loud startling stimulus (termed the “pulse”) is preceded by a quieter nonstartling stimulus (termed a “prepulse”) at short stimulus onset asynchronies , and represents an operational measure of sensorimotor gating , . However, other studies have been shown that PPI is not a completely automatic process; it occurs involuntarily but can be modulated by controlled attentional processes and has been used as a tool for investigating attention , .
We found that compared with the control group, the exposure to MPH didn't significantly alter PPI. Thus, it appears that allegedly MPH has no effect in “normal” conditions. However, while the exposure to EE led to the highest PPI rate, subsequent MPH treatment significantly impaired attentiveness. Similarly, the exposure to mild stress was associated with intermediate PPI levels (higher than the control but lower than EE), that were reduced by the presence of MPH.
Taken together, the results of the PPI test indicate that when MPH treatment is superfluous (i.e; without clear indication of ADD/ADHD), it may bare no effect or even paradoxly impairs attentiveness. It should be noted that previous studies which evaluated behavioral alterations following the exposure to pre-pubertal MPH, did not measure changes in attentiveness –.
In order to better understand the behavioral consequences of MPH treatment, we first measured serum CORT level. It has been shown previously that MPH treatment leads to increased levels of CORT , . Likewise, we found that long term MPH administration elevated CORT to a marked degree, but only in the EE and EES groups. Thus, we suggest that adolescence EE together with early adulthood MPH abuse may act as a predisposition for the development of possible stressful behaviors in adulthood.
Studies of the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-testicular (HPT) axis revealed a reciprocal relationship between these two endocrine pathways, in which CORT increases the negative feedback effects of TST –. Therefore, the observed high level of CORT subsequent to MPH treatment is expected to be accompanied by a low level of TST. Consequently, we found a surprising elevation of TST level following MPH administration in the EE and EES groups. Hence, adolescence EE followed by MPH treatment during early adulthood, impaired the expected natural level balance between the two hormones, and overall led to long term hormonal agitation.
Furthermore, TST was found to elicit aggressive behavior in children, juvenile and adult males, in both rats and humans –. However, among ADHD treated patients, MPH was found to reduce aggression , . Together with our finding, a “pro-aggression” effect of MPH may be observed when given to subjects without ADD/ADHD (i.e., abuse).
Thus, we suggest that a distinction should be made between justified medical consumption of MPH, which leads to beneficial effects, and MPH abuse that may lead to increased arousal and aggression. Additionally, it raises ethical questions regarding reports on the use of MPH as a “Cognitive Enhancing drug” in non-medical situations (i,e; shift work, military personnel, etc.) .
Our study demonstrates for the first time the long term effects of MPH treatment (in a non-ADD/ADHD condition) in the context of various life experiences. Following adolescence EE, MPH had deteriorating behavioral and hormonal effects. Adding stress in adulthood restored only the behavioral effects, while both corticosterone and testosterone levels remained high. Therefore, in non-ADHD subjects, MPH allegedly has no overt (behavioral) effects, while covertly (hormonal) it has robust and long lasting effects. Future studies may further the hormonal effects by exploring changes in behaviors related to aggression and response to rewarding stimuli (such as cocaine self administration).
Thus, cautious decision making while prescribing MPH is required in order to prevent its harmful social long-term consequences.
Conceived and designed the experiments: AA. Performed the experiments: TD SA-M SZ. Analyzed the data: AA TD SZ. Contributed reagents/materials/analysis tools: AA. Wrote the paper: AA TD SA-M.
- 1. Aron AR, Dowson JH, Sahakian BJ, Robbins TW (2003) Methylphenidate improves response inhibition in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry 54: 1465–1468.AR AronJH DowsonBJ SahakianTW Robbins2003Methylphenidate improves response inhibition in adults with attention-deficit/hyperactivity disorder.Biol Psychiatry5414651468
- 2. Hawk LW Jr, Yartz AR, Pelham WE Jr, Lock TM (2003) The effects of methylphenidate on prepulse inhibition during attended and ignored prestimuli among boys with attention-deficit hyperactivity disorder. Psychopharmacology (Berl) 165: 118–127.LW Hawk JrAR YartzWE Pelham JrTM Lock2003The effects of methylphenidate on prepulse inhibition during attended and ignored prestimuli among boys with attention-deficit hyperactivity disorder.Psychopharmacology (Berl)165118127
- 3. Abikoff H, Hechtman L, Klein RG, Weiss G, Fleiss K, et al. (2004) Symptomatic improvement in children with ADHD treated with long-term methylphenidate and multimodal psychosocial treatment. J Am Acad Child Adolesc Psychiatry 43: 802–811.H. AbikoffL. HechtmanRG KleinG. WeissK. Fleiss2004Symptomatic improvement in children with ADHD treated with long-term methylphenidate and multimodal psychosocial treatment.J Am Acad Child Adolesc Psychiatry43802811
- 4. Mehta MA, Goodyer IM, Sahakian BJ (2004) Methylphenidate improves working memory and set-shifting in AD/HD: relationships to baseline memory capacity. J Child Psychol Psychiatry 45: 293–305.MA MehtaIM GoodyerBJ Sahakian2004Methylphenidate improves working memory and set-shifting in AD/HD: relationships to baseline memory capacity.J Child Psychol Psychiatry45293305
- 5. Volkow ND, Wang GJ, Fowler JS, Gatley SJ, Logan J, et al. (1998) Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry 155: 1325–1331.ND VolkowGJ WangJS FowlerSJ GatleyJ. Logan1998Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate.Am J Psychiatry15513251331
- 6. Anderson VR, Scott LJ (2006) Methylphenidate transdermal system: In attention-deficit hyperactivity disorder in children. Drugs 66: 1117–1126.VR AndersonLJ Scott2006Methylphenidate transdermal system: In attention-deficit hyperactivity disorder in children.Drugs6611171126
- 7. Hannestad J, Gallezot JD, Planeta-Wilson B, Lin SF, Williams WA, et al. (2010) Clinically relevant doses of methylphenidate significantly occupy norepinephrine transporters in humans in vivo. Biol Psychiatry 68: 854–860.J. HannestadJD GallezotB. Planeta-WilsonSF LinWA Williams2010Clinically relevant doses of methylphenidate significantly occupy norepinephrine transporters in humans in vivo.Biol Psychiatry68854860
- 8. Teicher MH, Ito Y, Glod CA, Barber NI (1996) Objective measurement of hyperactivity and attentional problems in ADHD. J Am Acad Child Adolesc Psychiatry 35: 334–342.MH TeicherY. ItoCA GlodNI Barber1996Objective measurement of hyperactivity and attentional problems in ADHD.J Am Acad Child Adolesc Psychiatry35334342
- 9. Nass RD (2005) Evaluation and assessment issues in the diagnosis of attention deficit hyperactivity disorder. Semin Pediatr Neurol 12: 200–216.RD Nass2005Evaluation and assessment issues in the diagnosis of attention deficit hyperactivity disorder.Semin Pediatr Neurol12200216
- 10. Rey JM, Sawyer MG (2003) Are psychostimulant drugs being used appropriately to treat child and adolescent disorders? Br J Psychiatry 182: 284–286.JM ReyMG Sawyer2003Are psychostimulant drugs being used appropriately to treat child and adolescent disorders?Br J Psychiatry182284286
- 11. Poulin C (2001) Medical and nonmedical stimulant use among adolescents: from sanctioned to unsanctioned use. CMAJ 165: 1039–1044.C. Poulin2001Medical and nonmedical stimulant use among adolescents: from sanctioned to unsanctioned use.CMAJ16510391044
- 12. Rose S (2008) Drugging unruly children is a method of social control. Nature 451: 521.S. Rose2008Drugging unruly children is a method of social control.Nature451521
- 13. Miller KJ, Castellanos FX (1998) Attention deficit/hyperactivity disorders. Pediatr Rev 19: 373–384.KJ MillerFX Castellanos1998Attention deficit/hyperactivity disorders.Pediatr Rev19373384
- 14. Kirby K, Rutman LE, Bernstein H (2002) Attention-deficit/hyperactivity disorder: a therapeutic update. Curr Opin Pediatr 14: 236–246.K. KirbyLE RutmanH. Bernstein2002Attention-deficit/hyperactivity disorder: a therapeutic update.Curr Opin Pediatr14236246
- 15. Zito JM, Safer DJ, dosReis S, Gardner JF, Boles M, et al. (2000) Trends in the prescribing of psychotropic medications to preschoolers. JAMA 283: 1025–1030.JM ZitoDJ SaferS. dosReisJF GardnerM. Boles2000Trends in the prescribing of psychotropic medications to preschoolers.JAMA28310251030
- 16. Jensen PS, Kettle L, Roper MT, Sloan MT, Dulcan MK, et al. (1999) Are stimulants overprescribed? Treatment of ADHD in four U.S. communities. J Am Acad Child Adolesc Psychiatry 38: 797–804.PS JensenL. KettleMT RoperMT SloanMK Dulcan1999Are stimulants overprescribed? Treatment of ADHD in four U.S. communities.J Am Acad Child Adolesc Psychiatry38797804
- 17. Williams RJ, Goodale LA, Shay-Fiddler MA, Gloster SP, Chang SY (2004) Methylphenidate and dextroamphetamine abuse in substance-abusing adolescents. Am J Addict 13: 381–389.RJ WilliamsLA GoodaleMA Shay-FiddlerSP GlosterSY Chang2004Methylphenidate and dextroamphetamine abuse in substance-abusing adolescents.Am J Addict13381389
- 18. Forrester MB (2006) Methylphenidate abuse in Texas, 1998–2004. J Toxicol Environ Health A 69: 1145–1153.MB Forrester2006Methylphenidate abuse in Texas, 1998–2004.J Toxicol Environ Health A6911451153
- 19. Bright GM (2008) Abuse of medications employed for the treatment of ADHD: results from a large-scale community survey. Medscape J Med 10: 111.GM Bright2008Abuse of medications employed for the treatment of ADHD: results from a large-scale community survey.Medscape J Med10111
- 20. Teter CJ, McCabe SE, LaGrange K, Cranford JA, Boyd CJ (2006) Illicit use of specific prescription stimulants among college students: prevalence, motives, and routes of administration. Pharmacotherapy 26: 1501–1510.CJ TeterSE McCabeK. LaGrangeJA CranfordCJ Boyd2006Illicit use of specific prescription stimulants among college students: prevalence, motives, and routes of administration.Pharmacotherapy2615011510
- 21. Sahakian B, Morein-Zamir S (2007) Professor's little helper. Nature 450: 1157–1159.B. SahakianS. Morein-Zamir2007Professor's little helper.Nature45011571159
- 22. Svetlov SI, Kobeissy FH, Gold MS (2007) Performance enhancing, non-prescription use of Ritalin: a comparison with amphetamines and cocaine. J Addict Dis 26: 1–6.SI SvetlovFH KobeissyMS Gold2007Performance enhancing, non-prescription use of Ritalin: a comparison with amphetamines and cocaine.J Addict Dis2616
- 23. Swanson JM, Volkow ND (2008) Increasing use of stimulants warns of potential abuse. Nature 453: 586.JM SwansonND Volkow2008Increasing use of stimulants warns of potential abuse.Nature453586
- 24. Bogle KE, Smith BH (2009) Illicit methylphenidate use: a review of prevalence, availability, pharmacology, and consequences. Curr Drug Abuse Rev 2: 157–176.KE BogleBH Smith2009Illicit methylphenidate use: a review of prevalence, availability, pharmacology, and consequences.Curr Drug Abuse Rev2157176
- 25. Basu P (2006) Addictive drugs still best option for attention deficit disorder. Nat Med 12: 374.P. Basu2006Addictive drugs still best option for attention deficit disorder.Nat Med12374
- 26. Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24: 417–463.LP Spear2000The adolescent brain and age-related behavioral manifestations.Neurosci Biobehav Rev24417463
- 27. Spear L (2000) Modeling adolescent development and alcohol use in animals. Alcohol Res Health 24: 115–123.L. Spear2000Modeling adolescent development and alcohol use in animals.Alcohol Res Health24115123
- 28. Laviola G, Macri S, Morley-Fletcher S, Adriani W (2003) Risk-taking behavior in adolescent mice: psychobiological determinants and early epigenetic influence. Neurosci Biobehav Rev 27: 19–31.G. LaviolaS. MacriS. Morley-FletcherW. Adriani2003Risk-taking behavior in adolescent mice: psychobiological determinants and early epigenetic influence.Neurosci Biobehav Rev271931
- 29. Marco EM, Adriani W, Ruocco LA, Sadile AG, Laviola G (2011) Neurobehavioral adaptations to methylphenidate: The issue of early adolescent exposure. Neurosci Biobehav Rev. EM MarcoW. AdrianiLA RuoccoAG SadileG. Laviola2011Neurobehavioral adaptations to methylphenidate: The issue of early adolescent exposure.Neurosci Biobehav Rev
- 30. Bolanos CA, Barrot M, Berton O, Wallace-Black D, Nestler EJ (2003) Methylphenidate treatment during pre- and periadolescence alters behavioral responses to emotional stimuli at adulthood. Biol Psychiatry 54: 1317–1329.CA BolanosM. BarrotO. BertonD. Wallace-BlackEJ Nestler2003Methylphenidate treatment during pre- and periadolescence alters behavioral responses to emotional stimuli at adulthood.Biol Psychiatry5413171329
- 31. Carlezon WA Jr, Mague SD, Andersen SL (2003) Enduring behavioral effects of early exposure to methylphenidate in rats. Biol Psychiatry 54: 1330–1337.WA Carlezon JrSD MagueSL Andersen2003Enduring behavioral effects of early exposure to methylphenidate in rats.Biol Psychiatry5413301337
- 32. Mague SD, Andersen SL, Carlezon WA Jr (2005) Early developmental exposure to methylphenidate reduces cocaine-induced potentiation of brain stimulation reward in rats. Biol Psychiatry 57: 120–125.SD MagueSL AndersenWA Carlezon Jr2005Early developmental exposure to methylphenidate reduces cocaine-induced potentiation of brain stimulation reward in rats.Biol Psychiatry57120125
- 33. Lagace DC, Yee JK, Bolanos CA, Eisch AJ (2006) Juvenile administration of methylphenidate attenuates adult hippocampal neurogenesis. Biol Psychiatry 60: 1121–1130.DC LagaceJK YeeCA BolanosAJ Eisch2006Juvenile administration of methylphenidate attenuates adult hippocampal neurogenesis.Biol Psychiatry6011211130
- 34. Avital A, Richter-Levin G, Leschiner S, Spanier I, Veenman L, et al. (2001) Acute and repeated swim stress effects on peripheral benzodiazepine receptors in the rat hippocampus, adrenal, and kidney. Neuropsychopharmacology 25: 669–678.A. AvitalG. Richter-LevinS. LeschinerI. SpanierL. Veenman2001Acute and repeated swim stress effects on peripheral benzodiazepine receptors in the rat hippocampus, adrenal, and kidney.Neuropsychopharmacology25669678
- 35. Avital A, Segal M, Richter-Levin G (2006) Contrasting roles of corticosteroid receptors in hippocampal plasticity. J Neurosci 26: 9130–9134.A. AvitalM. SegalG. Richter-Levin2006Contrasting roles of corticosteroid receptors in hippocampal plasticity.J Neurosci2691309134
- 36. Avital A, Ram E, Maayan R, Weizman A, Richter-Levin G (2006) Effects of early-life stress on behavior and neurosteroid levels in the rat hypothalamus and entorhinal cortex. Brain Res Bull 68: 419–424.A. AvitalE. RamR. MaayanA. WeizmanG. Richter-Levin2006Effects of early-life stress on behavior and neurosteroid levels in the rat hypothalamus and entorhinal cortex.Brain Res Bull68419424
- 37. Smith C (2011) The effects of Sceletium tortuosum in an in vivo model of psychological stress. J Ethnopharmacol 133: 31–36.C. Smith2011The effects of Sceletium tortuosum in an in vivo model of psychological stress.J Ethnopharmacol1333136
- 38. Belz EE, Kennell JS, Czambel RK, Rubin RT, Rhodes ME (2003) Environmental enrichment lowers stress-responsive hormones in singly housed male and female rats. Pharmacol Biochem Behav 76: 481–486.EE BelzJS KennellRK CzambelRT RubinME Rhodes2003Environmental enrichment lowers stress-responsive hormones in singly housed male and female rats.Pharmacol Biochem Behav76481486
- 39. Benaroya-Milshtein N, Hollander N, Apter A, Kukulansky T, Raz N, et al. (2004) Environmental enrichment in mice decreases anxiety, attenuates stress responses and enhances natural killer cell activity. Eur J Neurosci 20: 1341–1347.N. Benaroya-MilshteinN. HollanderA. ApterT. KukulanskyN. Raz2004Environmental enrichment in mice decreases anxiety, attenuates stress responses and enhances natural killer cell activity.Eur J Neurosci2013411347
- 40. Ferguson SA, Boctor SY (2010) Cocaine responsiveness or anhedonia in rats treated with methylphenidate during adolescence. Neurotoxicol Teratol 32: 432–442.SA FergusonSY Boctor2010Cocaine responsiveness or anhedonia in rats treated with methylphenidate during adolescence.Neurotoxicol Teratol32432442
- 41. Schaefer TL, Ehrman LA, Gudelsky GA, Vorhees CV, Williams MT (2006) Comparison of monoamine and corticosterone levels 24 h following (+)methamphetamine, (+/−)3,4-methylenedioxymethamphetamine, cocaine, (+)fenfluramine or (+/−)methylphenidate administration in the neonatal rat. J Neurochem 98: 1369–1378.TL SchaeferLA EhrmanGA GudelskyCV VorheesMT Williams2006Comparison of monoamine and corticosterone levels 24 h following (+)methamphetamine, (+/−)3,4-methylenedioxymethamphetamine, cocaine, (+)fenfluramine or (+/−)methylphenidate administration in the neonatal rat.J Neurochem9813691378
- 42. King S, Waschbusch DA, Pelham WE Jr, Frankland BW, Andrade BF, et al. (2009) Social information processing in elementary-school aged children with ADHD: medication effects and comparisons with typical children. J Abnorm Child Psychol 37: 579–589.S. KingDA WaschbuschWE Pelham JrBW FranklandBF Andrade2009Social information processing in elementary-school aged children with ADHD: medication effects and comparisons with typical children.J Abnorm Child Psychol37579589
- 43. Sinzig J, Dopfner M, Lehmkuhl G, Uebel H, et al. German Methylphenidate Study Group (2007) Long-acting methylphenidate has an effect on aggressive behavior in children with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 17: 421–432.J. SinzigM. DopfnerG. LehmkuhlH. UebelGerman Methylphenidate Study Group2007Long-acting methylphenidate has an effect on aggressive behavior in children with attention-deficit/hyperactivity disorder.J Child Adolesc Psychopharmacol17421432
- 44. van Bokhoven I, van Goozen SH, van Engeland H, Schaal B, Arseneault L, et al. (2006) Salivary testosterone and aggression, delinquency, and social dominance in a population-based longitudinal study of adolescent males. Horm Behav 50: 118–125.I. van BokhovenSH van GoozenH. van EngelandB. SchaalL. Arseneault2006Salivary testosterone and aggression, delinquency, and social dominance in a population-based longitudinal study of adolescent males.Horm Behav50118125
- 45. Soma KK (2006) Testosterone and aggression: Berthold, birds and beyond. J Neuroendocrinol 18: 543–551.KK Soma2006Testosterone and aggression: Berthold, birds and beyond.J Neuroendocrinol18543551
- 46. Mehta PH, Beer J (2010) Neural mechanisms of the testosterone-aggression relation: the role of orbitofrontal cortex. J Cogn Neurosci 22: 2357–2368.PH MehtaJ. Beer2010Neural mechanisms of the testosterone-aggression relation: the role of orbitofrontal cortex.J Cogn Neurosci2223572368
- 47. Hermans EJ, Ramsey NF, van Honk J (2008) Exogenous testosterone enhances responsiveness to social threat in the neural circuitry of social aggression in humans. Biol Psychiatry 63: 263–270.EJ HermansNF RamseyJ. van Honk2008Exogenous testosterone enhances responsiveness to social threat in the neural circuitry of social aggression in humans.Biol Psychiatry63263270
- 48. Buitelaar J, Medori R (2010) Treating attention-deficit/hyperactivity disorder beyond symptom control alone in children and adolescents: a review of the potential benefits of long-acting stimulants. Eur Child Adolesc Psychiatry 19: 325–340.J. BuitelaarR. Medori2010Treating attention-deficit/hyperactivity disorder beyond symptom control alone in children and adolescents: a review of the potential benefits of long-acting stimulants.Eur Child Adolesc Psychiatry19325340
- 49. Angold A, Erkanli A, Egger HL, Costello EJ (2000) Stimulant treatment for children: a community perspective. J Am Acad Child Adolesc Psychiatry 39: 975–84; discussion 984–94.A. AngoldA. ErkanliHL EggerEJ Costello2000Stimulant treatment for children: a community perspective.J Am Acad Child Adolesc Psychiatry3997584; discussion 984–94
- 50. Zhang H, Du M, Zhuang S (2010) Impact of Long-Term Treatment of Methylphenidate on Height and Weight of School Age Children with ADHD. Neuropediatrics 41: 55–59.H. ZhangM. DuS. Zhuang2010Impact of Long-Term Treatment of Methylphenidate on Height and Weight of School Age Children with ADHD.Neuropediatrics415559
- 51. Britton GB, Segan AT, Sejour J, Mancebo SE (2007) Early exposure to methylphenidate increases fear responses in an aversive context in adult rats. Dev Psychobiol 49: 265–275.GB BrittonAT SeganJ. SejourSE Mancebo2007Early exposure to methylphenidate increases fear responses in an aversive context in adult rats.Dev Psychobiol49265275
- 52. Chapillon P, Manneche C, Belzung C, Caston J (1999) Rearing environmental enrichment in two inbred strains of mice: 1. Effects on emotional reactivity. Behav Genet 29: 41–46.P. ChapillonC. MannecheC. BelzungJ. Caston1999Rearing environmental enrichment in two inbred strains of mice: 1. Effects on emotional reactivity.Behav Genet294146
- 53. Ilin Y, Richter-Levin G (2009) Enriched environment experience overcomes learning deficits and depressive-like behavior induced by juvenile stress. PLoS One 4: e4329.Y. IlinG. Richter-Levin2009Enriched environment experience overcomes learning deficits and depressive-like behavior induced by juvenile stress.PLoS One4e4329
- 54. Varty GB, Paulus MP, Braff DL, Geyer MA (2000) Environmental enrichment and isolation rearing in the rat: effects on locomotor behavior and startle response plasticity. Biol Psychiatry 47: 864–873.GB VartyMP PaulusDL BraffMA Geyer2000Environmental enrichment and isolation rearing in the rat: effects on locomotor behavior and startle response plasticity.Biol Psychiatry47864873
- 55. Branchi I, Alleva E (2006) Communal nesting, an early social enrichment, increases the adult anxiety-like response and shapes the role of social context in modulating the emotional behavior. Behav Brain Res 172: 299–306.I. BranchiE. Alleva2006Communal nesting, an early social enrichment, increases the adult anxiety-like response and shapes the role of social context in modulating the emotional behavior.Behav Brain Res172299306
- 56. Kohl Z, Kuhn HG, Cooper-Kuhn CM, Winkler J, Aigner L, et al. (2002) Preweaning enrichment has no lasting effects on adult hippocampal neurogenesis in four-month-old mice. Genes Brain Behav 1: 46–54.Z. KohlHG KuhnCM Cooper-KuhnJ. WinklerL. Aigner2002Preweaning enrichment has no lasting effects on adult hippocampal neurogenesis in four-month-old mice.Genes Brain Behav14654
- 57. Frick KM, Fernandez SM (2003) Enrichment enhances spatial memory and increases synaptophysin levels in aged female mice. Neurobiol Aging 24: 615–626.KM FrickSM Fernandez2003Enrichment enhances spatial memory and increases synaptophysin levels in aged female mice.Neurobiol Aging24615626
- 58. Bruel-Jungerman E, Laroche S, Rampon C (2005) New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment. Eur J Neurosci 21: 513–521.E. Bruel-JungermanS. LarocheC. Rampon2005New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment.Eur J Neurosci21513521
- 59. Tang YP, Wang H, Feng R, Kyin M, Tsien JZ (2001) Differential effects of enrichment on learning and memory function in NR2B transgenic mice. Neuropharmacology 41: 779–790.YP TangH. WangR. FengM. KyinJZ Tsien2001Differential effects of enrichment on learning and memory function in NR2B transgenic mice.Neuropharmacology41779790
- 60. Pham TM, Ickes B, Albeck D, Soderstrom S, Granholm AC, et al. (1999) Changes in brain nerve growth factor levels and nerve growth factor receptors in rats exposed to environmental enrichment for one year. Neuroscience 94: 279–286.TM PhamB. IckesD. AlbeckS. SoderstromAC Granholm1999Changes in brain nerve growth factor levels and nerve growth factor receptors in rats exposed to environmental enrichment for one year.Neuroscience94279286
- 61. Amaral OB, Vargas RS, Hansel G, Izquierdo I, Souza DO (2008) Duration of environmental enrichment influences the magnitude and persistence of its behavioral effects on mice. Physiol Behav 93: 388–394.OB AmaralRS VargasG. HanselI. IzquierdoDO Souza2008Duration of environmental enrichment influences the magnitude and persistence of its behavioral effects on mice.Physiol Behav93388394
- 62. Morley-Fletcher S, Rea M, Maccari S, Laviola G (2003) Environmental enrichment during adolescence reverses the effects of prenatal stress on play behaviour and HPA axis reactivity in rats. Eur J Neurosci 18: 3367–3374.S. Morley-FletcherM. ReaS. MaccariG. Laviola2003Environmental enrichment during adolescence reverses the effects of prenatal stress on play behaviour and HPA axis reactivity in rats.Eur J Neurosci1833673374
- 63. Cui M, Yang Y, Yang J, Zhang J, Han H, et al. (2006) Enriched environment experience overcomes the memory deficits and depressive-like behavior induced by early life stress. Neurosci Lett 404: 208–212.M. CuiY. YangJ. YangJ. ZhangH. Han2006Enriched environment experience overcomes the memory deficits and depressive-like behavior induced by early life stress.Neurosci Lett404208212
- 64. Veena J, Srikumar BN, Raju TR, Shankaranarayana Rao BS (2009) Exposure to enriched environment restores the survival and differentiation of new born cells in the hippocampus and ameliorates depressive symptoms in chronically stressed rats. Neurosci Lett 455: 178–182.J. VeenaBN SrikumarTR RajuBS Shankaranarayana Rao2009Exposure to enriched environment restores the survival and differentiation of new born cells in the hippocampus and ameliorates depressive symptoms in chronically stressed rats.Neurosci Lett455178182
- 65. Bolanos CA, Willey MD, Maffeo ML, Powers KD, Kinka DW, et al. (2008) Antidepressant treatment can normalize adult behavioral deficits induced by early-life exposure to methylphenidate. Biol Psychiatry 63: 309–316.CA BolanosMD WilleyML MaffeoKD PowersDW Kinka2008Antidepressant treatment can normalize adult behavioral deficits induced by early-life exposure to methylphenidate.Biol Psychiatry63309316
- 66. Quinn R (2005) Comparing rat's to human's age: how old is my rat in people years? Nutrition 21: 775–777.R. Quinn2005Comparing rat's to human's age: how old is my rat in people years?Nutrition21775777
- 67. Leggio MG, Mandolesi L, Federico F, Spirito F, Ricci B, et al. (2005) Environmental enrichment promotes improved spatial abilities and enhanced dendritic growth in the rat. Behav Brain Res 163: 78–90.MG LeggioL. MandolesiF. FedericoF. SpiritoB. Ricci2005Environmental enrichment promotes improved spatial abilities and enhanced dendritic growth in the rat.Behav Brain Res1637890
- 68. Degroot A, Wolff MC, Nomikos GG (2005) Acute exposure to a novel object during consolidation enhances cognition. Neuroreport 16: 63–67.A. DegrootMC WolffGG Nomikos2005Acute exposure to a novel object during consolidation enhances cognition.Neuroreport166367
- 69. Graham FK (1975) Presidential Address, 1974. The more or less startling effects of weak prestimulation. Psychophysiology 12: 238–248.FK Graham1975Presidential Address, 1974. The more or less startling effects of weak prestimulation.Psychophysiology12238248
- 70. Hart S, Zreik M, Carper R, Swerdlow NR (1998) Localizing haloperidol effects on sensorimotor gating in a predictive model of antipsychotic potency. Pharmacol Biochem Behav 61: 113–119.S. HartM. ZreikR. CarperNR Swerdlow1998Localizing haloperidol effects on sensorimotor gating in a predictive model of antipsychotic potency.Pharmacol Biochem Behav61113119
- 71. Palsson E, Soderlund G, Klamer D, Bergquist F (2011) Noise benefit in prepulse inhibition of the acoustic startle reflex. Psychopharmacology (Berl) 214: 675–685.E. PalssonG. SoderlundD. KlamerF. Bergquist2011Noise benefit in prepulse inhibition of the acoustic startle reflex.Psychopharmacology (Berl)214675685
- 72. Scholes KE, Martin-Iverson MT (2010) Disturbed prepulse inhibition in patients with schizophrenia is consequential to dysfunction of selective attention. Psychophysiology 47: 223–235.KE ScholesMT Martin-Iverson2010Disturbed prepulse inhibition in patients with schizophrenia is consequential to dysfunction of selective attention.Psychophysiology47223235
- 73. Weiss IC, Domeney AM, Moreau JL, Russig H, Feldon J (2001) Dissociation between the effects of pre-weaning and/or post-weaning social isolation on prepulse inhibition and latent inhibition in adult Sprague–Dawley rats. Behav Brain Res 121: 207–218.IC WeissAM DomeneyJL MoreauH. RussigJ. Feldon2001Dissociation between the effects of pre-weaning and/or post-weaning social isolation on prepulse inhibition and latent inhibition in adult Sprague–Dawley rats.Behav Brain Res121207218
- 74. Vreeburg JT, de Greef WJ, Ooms MP, van Wouw P, Weber RF (1984) Effects of adrenocorticotropin and corticosterone on the negative feedback action of testosterone in the adult male rat. Endocrinology 115: 977–983.JT VreeburgWJ de GreefMP OomsP. van WouwRF Weber1984Effects of adrenocorticotropin and corticosterone on the negative feedback action of testosterone in the adult male rat.Endocrinology115977983
- 75. Vreeburg JT, Samaun K, Verkade HJ, Verhoef P, Ooms MP, et al. (1988) Effects of corticosterone on the negative feedback action of testosterone, 5 alpha-dihydrotestosterone and estradiol in the adult male rat. J Steroid Biochem 29: 93–98.JT VreeburgK. SamaunHJ VerkadeP. VerhoefMP Ooms1988Effects of corticosterone on the negative feedback action of testosterone, 5 alpha-dihydrotestosterone and estradiol in the adult male rat.J Steroid Biochem299398
- 76. Bonilla-Jaime H, Retana-Marquez S, Vazquez-Palacios G, Velazquez-Moctezuma J (2003) Corticosterone and testosterone levels after chronic stress in an animal model of depression. Neuropsychobiology 48: 55–58.H. Bonilla-JaimeS. Retana-MarquezG. Vazquez-PalaciosJ. Velazquez-Moctezuma2003Corticosterone and testosterone levels after chronic stress in an animal model of depression.Neuropsychobiology485558
- 77. Waite E, Kershaw Y, Spiga F, Lightman SL (2009) A glucocorticoid sensitive biphasic rhythm of testosterone secretion. J Neuroendocrinol 21: 737–741.E. WaiteY. KershawF. SpigaSL Lightman2009A glucocorticoid sensitive biphasic rhythm of testosterone secretion.J Neuroendocrinol21737741
- 78. Carre JM, Gilchrist JD, Morrissey MD, McCormick CM (2010) Motivational and situational factors and the relationship between testosterone dynamics and human aggression during competition. Biol Psychol 84: 346–353.JM CarreJD GilchristMD MorrisseyCM McCormick2010Motivational and situational factors and the relationship between testosterone dynamics and human aggression during competition.Biol Psychol84346353
- 79. Frahm KA, Lumia AR, Fernandez E, Strong R, Roberts JL, et al. (2011) Effects of anabolic androgenic steroids and social subjugation on behavior and neurochemistry in male rats. Pharmacol Biochem Behav 97: 416–422.KA FrahmAR LumiaE. FernandezR. StrongJL Roberts2011Effects of anabolic androgenic steroids and social subjugation on behavior and neurochemistry in male rats.Pharmacol Biochem Behav97416422
- 80. Lumia AR, McGinnis MY (2010) Impact of anabolic androgenic steroids on adolescent males. Physiol Behav 100: 199–204.AR LumiaMY McGinnis2010Impact of anabolic androgenic steroids on adolescent males.Physiol Behav100199204
- 81. Sanchez-Martin JR, Azurmendi A, Pascual-Sagastizabal E, Cardas J, Braza F, et al. (2010) Androgen levels and anger and impulsivity measures as predictors of physical, verbal and indirect aggression in boys and girls. Psychoneuroendocrinology 36: 750–60.JR Sanchez-MartinA. AzurmendiE. Pascual-SagastizabalJ. CardasF. Braza2010Androgen levels and anger and impulsivity measures as predictors of physical, verbal and indirect aggression in boys and girls.Psychoneuroendocrinology3675060
- 82. Golubchik P, Sever J, Zalsman G, Weizman A (2008) Methylphenidate in the treatment of female adolescents with cooccurrence of attention deficit/hyperactivity disorder and borderline personality disorder: a preliminary open-label trial. Int Clin Psychopharmacol 23: 228–231.P. GolubchikJ. SeverG. ZalsmanA. Weizman2008Methylphenidate in the treatment of female adolescents with cooccurrence of attention deficit/hyperactivity disorder and borderline personality disorder: a preliminary open-label trial.Int Clin Psychopharmacol23228231