Access the full text.
Sign up today, get DeepDyve free for 14 days.
Loading next page...
/lp/springer-journals/impulsiveness-overactivity-and-poorer-sustained-attention-improve-by-vpp0Bcy3Gr
- Publisher
- Springer Journals
- Copyright
- Copyright © 2011 by Sagvolden; licensee BioMed Central Ltd.
- Subject
- Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
- eISSN
- 1744-9081
- DOI
- 10.1186/1744-9081-7-6
- pmid
- 21450079
- Publisher site
- See Article on Publisher Site
Abstract
Background: ADHD is currently defined as a cognitive/behavioral developmental disorder where all clinical criteria are behavioral. Overactivity, impulsiveness, and inattentiveness are presently regarded as the main clinical symptoms. There is no biological marker, but there is considerable evidence to suggest that ADHD behavior is associated with poor dopaminergic and noradrenergic modulation of neuronal circuits that involve the frontal lobes. The best validated animal model of ADHD, the Spontaneously Hypertensive Rat (SHR), shows pronounced overactivity, impulsiveness, and deficient sustained attention. The primary objective of the present research was to investigate behavioral effects of a range of doses of chronic l-amphetamine on ADHD-like symptoms in the SHR. Methods: The present study tested the behavioral effects of 0.75 and 2.2 mg l-amphetamine base/kg i.p. in male SHRs and their controls, the Wistar Kyoto rat (WKY). ADHD-like behavior was tested with a visual discrimination task measuring overactivity, impulsiveness and inattentiveness. Results: The striking impulsiveness, overactivity, and poorer sustained attention seen during baseline conditions in the SHR were improved by chronic treatment with l-amphetamine. The dose-response curves were, however, different for the different behaviors. Most significantly, the 0.75 mg/kg dose of l-amphetamine improved sustained attention without reducing overactivity and impulsiveness. The 2.2 mg/kg dose improved sustained attention as well as reduced SHR overactivity and impulsiveness. Discussion: The effects of l-amphetamine to reduce the behavioral symptoms of ADHD in the SHR were maintained over the 14 days of daily dosing with no evidence of tolerance developing. Background explain behavioral changes often described as response Attention-deficit/hyperactivity disorder (ADHD) is cur- disinhibition [6] or poor executive functioning [7]. rently defined as a cognitive developmental disorder ADHD is highly heritable and the genetic and neuro- where all clinical criteria are behavioral [1]. Overactivity, biological causes are likely to reside in brain catechola- impulsiveness, and inattentiveness are presently mines (for a review see [4]). Most likely, ADHD regarded as the main clinical symptoms. symptoms are associated with reduced post-synaptic efficacy of dopaminergic and noradrenergic modulation There have been many attempts to explain the origins of ADHD symptoms. A dual-process theory [2-5] sug- of neuronal circuits that involve the frontal lobes [8,9]. gests that less efficient reinforcement processes and defi- Imaging of striatal neuronal networks indicates reduced cient extinction of previously reinforced behavior may dopamine efficacy in ADHD [10]. Further, noradrenergic systems are involved in attention processes and prime prefrontal areas for response to sensory stimuli [11]. It is therefore not surprising that amphetamines and other Correspondence: terje.sagvolden@medisin.uio.no catecholamine agonists have been the drugs of choice in Institute of Basic Medical Sciences, Department of Physiology, University of Oslo, P.O. Box 1103 Blindern, NO-0317 Oslo, Norway © 2011 Sagvolden; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Sagvolden Behavioral and Brain Functions 2011, 7:6 Page 2 of 10 http://www.behavioralandbrainfunctions.com/content/7/1/6 medication of ADHD [8,9,12-14]. Although catechola- approved by the Norwegian Animal Research Authority mine agonists improve behavior, long-term academic (NARA), and were conducted in accordance with the performance is not improved to the same extent [14-18]. laws and regulations controlling experimental proce- The spontaneously hypertensive rat (SHR) is the best dures in live animals in Norway and the European validated animal model of ADHD. These rats show Union’s Directive 86/609/EEC. hyperactivity, impulsiveness and deficits in sustained attention [9,19-22]. The control strain is usually the Behavioral apparatus Wistar Kyoto Rat (WKY) as this rat is the progenitor Sixteen Campden Instruments operant chambers were strain and its behavior is closely similar to that of other used in the study. The animal’s working space in eight strains when tested in well-controlled operant tasks [20]. of the chambers was 25 × 25 × 30 (height) cm and 25 × Drugs used in the pharmacological treatment of ADHD, 25 × 20 (height) cm in the other eight chambers. A fan usually catecholamine agonists have been shown to producing a low masking noise and the 2.8-W house reduce ADHD-like behavior in this model [19,22-25]. light were on during the entire experimental session. Results from animal studies indicate that higher doses During training sessions, either no, one or both of amphetamines are required for reducing SHR overac- retractable levers were used (below). A 2.8-W cue light tivity and impulsiveness than those required for improv- was located above each lever. The rats’ response con- ing SHR sustained attention which, in children, is sisted of pressing one of the levers with a dead weight essential for long-term academic performance [22]. of at least 3 g to activate a micro-switch. The reinforcers Although d-amphetamine improves SHR overactivity (0.01 ml tap water) were delivered by a liquid dipper and impulsiveness as well as sustained attention, the located in a small recessed cubicle with a 2.8-W cue behavioral effects of l-amphetamine were relatively more light that lit up when a reinforcer was presented. A 7 × specific for improving sustained attention than for the 5 cm transparent plastic lid separated the cubicle from other two symptoms [22]. the rat’s working space. The rat could easily open the The primary objective of the present study was to test lid with a light push with the nose or paw. Each cham- the effects of chronic administration of 0.75 and 2.2 mg ber was ventilated and placed in a sound-resistant outer l-amphetamine base/kg i.p. to male SHRs and their con- housing. A computer and an online system (SPIDER, trols, the Wistar Kyoto rat (WKY), in a visual discrimi- Paul Fray, Ltd., UK) recorded the behavior and sched- nation task measuring overactivity, impulsiveness and uled reinforcers (drops of water). inattentiveness. Lower doses were used than in a pre- Before the initiation of the study, the rats were vious single-dose study [22]. assigned a chamber (1 through 16) and time of testing (10, 12 or 14 o’clock) in a randomized and balanced Methods way. The rat was returned to its living cage after each Subjects session and immediately given free access to water for A total number of 91 male rats, 47 SHR and 44 WKY, 60 min. participated in this study. At the start of testing follow- ing 3 days acclimatization, the rats were 5 wk old and Response acquisition experimentally naïve. Young rats were required, as The training period started with a single 30-min habi- ADHD primarily is a child and adolescent disorder. Due tuation session. During the habituation session, the lid to health status requirements, half of the SHRs were between the working space and the reinforcement cubi- obtained from Charles River Germany (SHR/NCrl), the cle was kept open. The house light was on, but no lever other half from Charles River Italy (SHR/NCrl). The was present, no cue light above any lever was lit and WKYs were from Charles River Germany (WKY/NCrl). water was not delivered. At the University of Oslo, the rats were housed indivi- The habituation session was followed by two dipper dually in 41 × 25 × 25 (height) cm transparent cages training sessions, lasting 30 and 15 min, respectively. and had free access to food (RM3 (E) from Special Diet The lid was taped open, no levers were present, and the Services, Witham, Essex CM8 3AD, UK). The rats had house light was on, but the cue lights above the levers access to water at all times before the habituation ses- were not lit. The computer delivered water on the aver- sion. Starting following completion of the habituation age every 10 s independent of the rat’s behavior (a vari- session, the rats were deprived of water for 21 hr a day; able-time schedule). Each water delivery was this is a moderate, but sufficient deprivation for motivat- accompanied by the turning on of the cue light in the ing the animal. The temperature in the housing area was small recessed cubicle. ~22°C. The light was on from 0700 to 1900 hours. The In the next two 30-min sessions, the rat was trained to behavioral training took place between 1000 and 1530 open the lid to gain access to the water. The lid was not hours seven days a week. The experiments were taped open, no levers were present and the lights above Sagvolden Behavioral and Brain Functions 2011, 7:6 Page 3 of 10 http://www.behavioralandbrainfunctions.com/content/7/1/6 the levers were not activated. The house light was on. consecutive correct responses (inter-response time, IRT) Each lid opening was followed by a presentation of a was also recorded. single drop of water. The cue light in the recessed cubi- The total number of lever presses is an expression of cle was turned on when water was present. the general activity level and therefore a measure of During the subsequent three to four sessions (depend- degree of activity. The percent choice of the correct lever ing on performance), lever responding was shaped by when the reinforcers are delivered infrequently is a mea- the method of successive approximations [26]. During sure of sustained attention [22]. The number of the initial sessions, the rats learned to press the left responses with short IRTs (< 0.67 s) is used as a measure lever in order to receive a reinforcer immediately follow- of degree of impulsiveness (cannot hold back a response ing every press. The cue light above the left lever was even when one knows it is an unnecessary one). now lit the entire session. The right lever was retracted into the wall. On the final session, the right lever was Drug administration activated and the left lever retracted. During this session The animals were randomly assigned to three treatment the light above the right lever was lit the entire session groups: 0.75 or 2.2 mg/kg l-amphetamine sulphate or and the light above the left lever was off. The house vehicle (physiological saline). Each rat was injected light was on during both sessions. Following this shap- intraperitoneally at a dose volume of 1 ml/kg body ing procedure, the animal had acquired the appropriate weight of the animal ~30 min before testing. The daily lever-pressing behavior. administration of the drug started at session 45 when From now on, both levers were present. The light the behavior had stabilized and ended at session 58 above the levers shifted randomly. The light stayed lit except for the saline groups that received 2.2 mg/kg above a lever for as long as it was the correct lever. This l-amphetamine ~30 min before sessions 59-61 in order was the discriminative stimulus showing the rat which to check that the drug response of these groups was the lever it had to press in order to receive a reinforcer. A same as their counterparts. concurrent extinction schedule was present on the wrong lever. There was never any light above the extinc- Drugs tion lever. Thus, the present task was a simultaneous l-Amphetamine sulphate (Lot FB-101-57) was supplied visual discrimination task. The seven sessions lasted for from Boeringer-Ingelheim US. Doses were calculated as 30 min and the reinforcers were delivered following the weight of base using a conversion factor of 1.360 mg every correct lever press. Whenever an interval had sulphate salt as equivalent to 1.000 mg base. Doses were elapsed, the reinforcer was delivered immediately follow- based on previously published data [22]. Dosing solu- ing the first correct response. tions were prepared in physiological saline. The drug solutions were prepared each day of dosing. Final schedule The simultaneous visual discrimination task was used Data management and statistical procedures for testing effects of the drugs. An unpredictable 180-s The mean behavior was regarded as the drug response. random-interval schedule was in effect for 90 min on The data were processed by univariate and multivariate the correct lever (signaled by a constantly lit cue light analyses of variance (ANOVAs and MANOVAs, respec- above this lever) from session 18 on until the study was tively) with the Statistica 7.1 program [28]. Strain and finished at session 61. Inter-reinforcer times ranged dose were between-subject variables coded as subgroups. from 6 to 719 s in a randomized fashion with a skewed One control rat fell ill early in the study and had to be distribution modeled after the “Harvard golden tape” sacrificed. Post-hoc comparisons following MANOVAs [27]. There was neither any external stimulus signaling were performed by the Newman-Keuls test. that a reinforcer was programmed, nor any external sti- mulus signaling the time since the last response. A con- Results current extinction schedule (never associated with any General cue light) was present on the wrong lever. The house Compared to WKY controls, SHRs showed poorer sus- light was lit the entire session. tained attention (Figure 1), pronounced overactivity (Figure 2), and impulsiveness (Figure 3) (see Additional Behavioral measures files 1 and 2). There were clear dose-response curves to Each session was divided into five 18-min segments l-amphetamine in the SHR, but the dose-response (parts) in order to monitor intra-session changes in the curves were different for the different behaviors. The behavior. For each segment, total number of presses on 0.75 mg/kg dose improved SHR sustained attention, the correct and incorrect lever as well as number of without reducing overactivity and impulsiveness. The reinforcers delivered were recorded. Time between 2.2 mg/kg dose improved attention, overactivity and Sagvolden Behavioral and Brain Functions 2011, 7:6 Page 4 of 10 http://www.behavioralandbrainfunctions.com/content/7/1/6 Figure 1 Effects of l-amphetamine on sustained attention, choice of the correct lever in percent of all lever presses, by SHR and WKY controls. Means ± SEM. Sessions 31 through 44 served as baseline sessions. Treatment was given at sessions 45 through 58. Sessions 59 through 61 were used for studying post-treatment effects, except for the groups that received vehicle (saline, 0 mg/kg) during treatment sessions 45-58. These groups received 2.2 mg/kg l-amphetamine to check for typical responsiveness to the drug for SHR and WKY. Figure 2 Effects of l-amphetamine on total number of lever presses (correct plus incorrect) by SHR and WKY controls. Means ± SEM. Sessions 31 through 44 served as baseline sessions. Treatment was given at sessions 45 through 58. Sessions 59 through 61 were used for studying post-treatment effects, except for the groups that received vehicle (saline, 0 mg/kg) during treatment sessions 45-58. These groups received 2.2 mg/kg l-amphetamine to check for typical responsiveness to the drug for SHR and WKY. Sagvolden Behavioral and Brain Functions 2011, 7:6 Page 5 of 10 http://www.behavioralandbrainfunctions.com/content/7/1/6 Figure 3 Effects of l-amphetamine on impulsiveness, responding within 0.67 s following the previous lever press, of SHR and WKY controls following log10 transformation. Means ± SEM. Sessions 31 through 44 served as baseline sessions. Treatment was given at sessions 45 through 58. Sessions 59 through 61 were used for studying post-treatment effects, except for the groups that received vehicle (saline, 0 mg/ kg) during treatment sessions 45-58. These groups received 2.2 mg/kg l-amphetamine to check for typical responsiveness to the drug for SHR and WKY. impulsiveness in the SHR. All of these effects were Sustained attention maintained over the 14 days of daily dosing. The effects Without medication, SHRs showed poorer sustained were only present during sessions with active drug. The attention than WKY controls. The three SHR subgroups drug had little effect on WKY behavior. were closely similar before the start of the injection pro- gram, as were the three WKY subgroups (Figure 1). Acquisition L-amphetamine produced a dose-related improvement in sustained attention in the SHR, but not in the WKY. As is thecaseinchildrenwith ADHD[29,30],the This improvement was maintained throughout the 14 symptoms in the SHR developed with time, but differ- day dosing period (sessions 45-58) (Figure 1). A similar ently for the different behaviors [21]. The final schedule effect of the 2.2 mg/kg dose was seen in the SHR sub- was installed on session 18. Sustained attention group which received vehicle (saline, 0 mg/kg) during improved in the WKY controls and stabilized at about session 30 (Figure 1). A pronounced overactivity was sessions 45 through 58 and then received the drug dur- seen in SHRs from session 18 onwards (Figure 2). SHR ing sessions 59 through 61 (Figures 1 and 4). The drug impulsiveness, responding within 0.67 s since the pre- effect did not transfer to sessions following the cessation vious lever press although such a lever press was rarely of drug administration. For the WKYs, 0.75 mg/kg reinforced, continued to increase in the SHR throughout l-amphetamine did not alter attentional behavior, but the entire study [21]. This measure was accompanied by the 2.2 mg/kg dose produced a slight deterioration in increased variability over days during the course of the behavior after dosing was terminated (Figure 4). study, something that is typical in ADHD [31-33]. Acute and chronic effects of l-amphetamine Impulsiveness was subjected to a log10-transformation The ANOVA comparing effects during pre-drug treat- in order to obtain the more equal variances required by ment (days 31 to 44) with effects during drug treatment the ANOVAs (Figure 3). For all three behaviors, the (days 45 to 58) showed a statistically significant main three SHR subgroups were closely similar before the effect of subgroup (F(3,87) = 14.62, p < 0.001). The start of the injection program. So were the three WKY MANOVA showed a main effect of treatment (F(1,87) = subgroups. 52.21, p < 0.001), a main effect of segment of session Sagvolden Behavioral and Brain Functions 2011, 7:6 Page 6 of 10 http://www.behavioralandbrainfunctions.com/content/7/1/6 Figure 4 This figure shows the mean within-session effects of l-amphetamine on sustained attention. Left panel: Sessions 31 through 44, baseline sessions. The three SHR subgroups are closely similar, so are the three WKY subgroups, prior to the injection program. Middle panel: Sessions 45 through 58, treatment sessions. Both doses improve SHR behavior. Right panel: Sessions 59 through 61, post-treatment sessions. The SHR subgroups return to pre-drug levels. The 2.2 mg/kg WKY subgroup apparently got worse following drug exposure. The WKY performance appears unaltered from pre- to post-treatment days. The groups that had received saline during sessions 45 through 58, now received 2.2 mg/kg. st nd (F(4,84) = 12.98, p < 0.001), a 2-way subgroup × treat- development from the 1 to the 2 half of the test per- ment interaction (F(3,87) = 6.63, p < 0.001), but no 3- iod. The subgroup × half test period interaction was: F way subgroup × treatment × segment interaction (F (3,58) = 0.96, p > 0.4). (12,223) = 1.36, p > 0.1). The acute drug effects in the subgroups receiving 2.2 mg/kg during sessions 59 Overactivity through 61 were compared to their behavior during ses- Without medication, SHRs showed a substantially sions 45 through 58, when they received saline, and higher activity than WKY controls. The three SHR sub- combined with the other animals of the same strain groups were closely similar before the start of the injec- receiving 2.2 mg/kg during sessions 45 through 58. tion program, as were the three WKY subgroups Thus, the drug had a larger effect in SHR than in WKY (Figures 2 and 5). L-amphetamine, 2.2 mg/kg, reduced controls (Figures 1 and 4). hyperactivity in the SHR, whilst having no effect on In order to check for the stability of the drug effects activity in the WKY. The improvement in the SHR was over the 14 days of daily dosing, the 14 treatment ses- maintained throughout the 14-day dosing period (Figure sions were divided into two halves, the initial seven ses- 2). A similar effect of the 2.2 mg/kg dose was seen in sions and the final seven sessions. The MANOVA of the the SHR subgroup which received vehicle (saline, 0 mg/ sustained attention behavior of the subgroups receiving kg) during sessions 45 through 58 and then received the an active dose showed no statistically significant drug during sessions 59 through 61 (Figures 2 and 5). Sagvolden Behavioral and Brain Functions 2011, 7:6 Page 7 of 10 http://www.behavioralandbrainfunctions.com/content/7/1/6 Figure 5 This figure shows the mean within-session effects of l-amphetamine on activity. Left panel: Sessions 31 through 44, baseline sessions. The three SHR subgroups are closely similar, so are the three WKY subgroups, prior to the injection program. Middle panel: Sessions 45 through 58, treatment sessions. 2.2 mg/kg reduces SHR overactivity. Right panel: Sessions 59 through 61, post-treatment sessions. The 2.2 mg/kg SHR subgroup returns to pre-drug levels. The WKY subgroups are apparently unaffected by the drug. The subgroups that had received saline during sessions 45 through 58, now received 2.2 mg/kg. The 2.2 mg/kg drug effect was not transferred to ses- the same strain receiving 2.2 mg/kg during sessions 45 sions following the cessation of drug administration. through 58. Thus, the results showed that the SHR The 0.75 mg/kg dose had no effect. There was no receiving 2.2 mg/kg had a larger effect in SHR than in apparent effect of the drug in the WKY controls. WKY controls (Figures 2 and 5). Acute and chronic effects of l-amphetamine Stability of the drug effects over the 14 days of daily The ANOVA showed a statistically significant main dosing was checked by dividing the 14 treatment ses- effect of subgroup (F(3,87) = 34.10, p < 0.001). The sions, into two halves, the initial seven sessions and the MANOVA showed a main effect of treatment (F(1,87) = final seven sessions. The MANOVA of the activity of 52.81, p < 0.001), a main effect of segment of session (F the subgroups receiving an active dose showed no statis- st nd (4,84) = 62.23, p < 0.001), a 2-way subgroup × treatment tically significant development from the 1 to the 2 interaction (F(3,87) = 34.20, p < 0.001), a 2-way sub- half of the test period. The subgroup × half test period group × segment of session interaction (F(12,223) = interaction was: F(3,58) = 1.70, p > 0.15. 6.35, p < 0.001), and a 3-way subgroup × treatment × segment interaction (F(12,223) = 5.91, p < 0.001). The Impulsiveness acute drug effects in the subgroups receiving 2.2 mg/kg Without medication, SHRs were substantially more during sessions 59 through 61 were compared to their impulsive than WKY controls. The three SHR sub- behavior during sessions 45 through 58, when they groups were closely similar before the start of the injec- received saline, and combined with the other animals of tion program, as were the three WKY subgroups Sagvolden Behavioral and Brain Functions 2011, 7:6 Page 8 of 10 http://www.behavioralandbrainfunctions.com/content/7/1/6 (Figures 3 and 6). L-amphetamine, 2.2 mg/kg, reduced × treatment interaction (F(3,87) = 3.77, p < 0.02), a 2- impulsiveness in the SHR, whilst having no effect in the way subgroup × segment of session interaction WKY. The improvement in impulsiveness was main- (F(12,223) = 2.73, p < 0.002), but no 3-way subgroup × tained throughout the 14-day dosing period (Figure 3). treatment × segment interaction (F(12,223) = 0.94, p > A similar effect of the 2.2 mg/kg dose was seen in the 0.5). The acute drug effects in the subgroups receiving SHR subgroup which received vehicle (saline, 0 mg/kg) 2.2 mg/kg during sessions 59 through 61 were compared during sessions 45 through 58 and then received the to their behavior during sessions 45 through 58, when drug during sessions 59 through 61 (Figure 3). The 0.75 they received saline, and combined with the other ani- mg/kg dose had no effect in any of the subgroups. The mals of the same strain receiving 2.2 mg/kg during ses- 2.2 mg/kg drug effect was not transferred to sessions sions 45 through 58. Thus, the results showed that the following the cessation of drug administration. SHR receiving 2.2 mg/kg had a larger effect in SHR Acute and chronic effects of l-amphetamine than in WKY controls (Figures 3 and 6). The ANOVA showed a statistically significant main Stability of the drug effects over the 14 days of daily effect of subgroup (F(3,87) = 10.00, p < 0.001). The dosing was checked by dividing the 14 treatment ses- MANOVA did not show a main effect of treatment sions into two halves, the initial seven sessions and the (F(1,87) = 2.96, p > 0.08), but a main effect of segment final seven sessions. The MANOVA of the impulsive- of session (F(4,84) = 32.31, p < 0.001), a 2-way subgroup ness of the subgroups receiving an active dose no Figure 6 This figure shows the mean within-session effects of l-amphetamine. Left panel: Sessions 31 through 44, baseline sessions. The three SHR subgroups are closely similar, so are the three WKY subgroups, prior to the injection program. Middle panel: Sessions 45 through 58, treatment sessions. The 2.2 mg/kg dose reduced SHR impulsiveness. Right panel: Sessions 59 through 61, post-treatment sessions. The 2.2 mg/ kg SHR subgroup returned to pre-drug levels. The 2.2 mg/kg WKY subgroup apparently got worse following drug exposure. The subgroups that had received saline during sessions 45 through 58, now received 2.2 mg/kg l-amphetamine. Sagvolden Behavioral and Brain Functions 2011, 7:6 Page 9 of 10 http://www.behavioralandbrainfunctions.com/content/7/1/6 st statistically significant development from the 1 to the reducing SHR overactivity and impulsiveness than those nd 2 half of the test period. The subgroup × half test per- required for improving SHR sustained attention. iod interaction was: F(3,58) = 1.27, p > 0.4. In conclusion, low doses of l-amphetamine improved sustained attention while higher doses improved sus- Reinforcers delivered tained attention as well as overactivity and impulsive- The random-interval reinforcement schedule used was ness in the SHR. These effects were maintained on programmed so that even large individual differences in chronic dosing. lever pressing would result in approximately 6 reinfor- cers (drops of water) during each 18-min segment of Additional material the session, even for the case of the less active group. A major advantage of such a schedule is the fact that sys- Additional file 1: The video shows a normal male WKY control rat performing the visual discrimination task. tematic strain differences in thirst should not be of con- Additional file 2: The video shows a Spontaneously Hypertensive cern when interpreting the data. The results show that Rat (SHR) performing the visual discrimination task. The rat is both strains in general also received 6 reinforcers per overactive and inattentive. segment during active drug. Stereotypy and severely drugged behavior Acknowledgements These doses of l-amphetamine did not produce stereo- Some of this research was financially supported by Shire Pharmaceutical typy or severely drugged behavior in the animals. Development LTD, England (Company No. 2486738), Hampshire International Business Park, Chineham, Basingstoke, Hampshire RG24 8EP, Great Britain. The research was also supported by grants from the University of Oslo and Discussion by The Centre for Advanced Study at the Norwegian Academy of Science ADHD is currently defined as a cognitive/behavioral and Letters, Drammensveien 78, NO-0271 Oslo, Norway. I am also grateful to Ms. Grete Wøien for her invaluable help in running the studies and to Dr. developmental disorder where all clinical criteria are Geir Sagvolden for writing the programs controlling the on-line system behavioral. Overactivity, impulsiveness, and inattentive- running the operant chambers and collecting the data. Expert technical ness are presently regarded as the main clinical symp- services were provided by Bjarne Authen. toms [1]. These symptoms have been operationalized in Competing interests a long series of translational research studies investigat- This research was in part financially supported by Shire Pharmaceutical ing ADHD behavior in children and animal models (e.g. Development LTD, England (Company No. 2486738), Hampshire International Business Park, Chineham, Basingstoke, Hampshire RG24 8EP, Great Britain. [30-35]). The company had no role, however, in the presentation of the research. ADHD is highly heritable and the genetic and neuro- Data presentation, statistics, discussion and conclusions that are the author’s biological causes are likely to reside in reduced postsy- own responsibility. naptic effects of catecholamines on glutamatergic and Received: 3 April 2008 Accepted: 30 March 2011 GABAergic neurons [4]. These changes apparently cause Published: 30 March 2011 less efficient reinforcement processes and deficient extinction of previously reinforced behavior [3-5]. References 1. American Psychiatric Association: Diagnostic and statistical manual of mental Amphetamines and other dopamine agonists have disorders: DSM-IV. 4 edition. Washington, D.C.: Author; 1994. been the drugs of choice in medication of ADHD 2. Sagvolden T, Archer T: Future perspectives on ADD research – An [8,9,12-14]. The primary objectives of the present irresistible challenge. In Attention deficit disorder: Clinical and basic research. Edited by: Sagvolden T, Archer T. Hillsdale, N.J.: Lawrence Erlbaum research were to test the behavioral effects of chronic Associates; 1989:369-389. administration of 0.75 and 2.2 mg/kg l-amphetamine in 3. Johansen EB, Aase H, Meyer A, Sagvolden T: Attention-deficit/hyperactivity SHRs and their controls, the Wistar Kyoto rat (WKY) in disorder (ADHD) behaviour explained by dysfunctioning reinforcement and extinction processes. Behav Brain Res 2002, 130:37-45. a visual discrimination task measuring overactivity, 4. Sagvolden T, Johansen EB, Aase H, Russell VA: A dynamic developmental impulsiveness and inattentiveness. theory of Attention-Deficit/Hyperactivity Disorder (ADHD) predominantly The results showed that both doses of l-amphetamine hyperactive/impulsive and combined subtypes. Behav Brain Sci 2005, 28:397-419. improved sustained attention in the SHR, but only the 5. Johansen EB, Sagvolden T, Aase H, Russell VA: The dynamic 2.2 mg/kg dose reduced SHR overactivity and impulsive- developmental theory of attention-deficit/hyperactivity disorder (ADHD): ness. These effects are similar to those seen previously Present status and future perspectives. Behav Brain Sci 2005, 28:451-454. 6. Barkley RA: Behavioral inhibition, sustained attention, and executive after acute administration of the drug [22]. The current functions: constructing a unifying theory of ADHD. Psychol Bull 1997, study has shown that these acute effects of l-ampheta- 121:65-94. mine are maintained with repeated daily dosing over 14 7. Tannock R: Attention deficit hyperactivity disorder: advances in cognitive, neurobiological, and genetic research. J Child Psychol Psychiatry days, with no evidence of tolerance developing. Results 1998, 39:65-99. from the present as well as a previous study [22] indi- 8. Arnsten AF, Dudley AG: Methylphenidate improves prefrontal cortical cate that higher doses of amphetamines are required for cognitive function through alpha2 adrenoceptor and dopamine D1 Sagvolden Behavioral and Brain Functions 2011, 7:6 Page 10 of 10 http://www.behavioralandbrainfunctions.com/content/7/1/6 receptor actions: Relevance to therapeutic effects in Attention Deficit 31. Aase H, Sagvolden T: Infrequent, but not frequent, reinforcers produce Hyperactivity Disorder. Behav Brain Funct 2005, 1:2. more variable responding and deficient sustained attention in young 9. Russell VA, Sagvolden T, Johansen EB: Animal models of attention-deficit children with attention-deficit/hyperactivity disorder (ADHD). J Child hyperactivity disorder. Behav Brain Funct 2005, 1:9. Psychol Psychiatry 2006, 47:457-471. 10. Ernst M, Zametkin AJ, Matochik JA, Jons PH, Cohen RM: DOPA 32. Aase H, Sagvolden T: Moment-to-moment dynamics of ADHD behaviour. decarboxylase activity in attention deficit hyperactivity disorder adults. Behav Brain Funct 2005, 1:12. A [fluorine-18]fluorodopa positron emission tomographic study. 33. Aase H, Meyer A, Sagvolden T: Moment-to-moment dynamics of ADHD J Neurosci 1998, 18:5901-5907. behaviour in South African children. Behav Brain Funct 2006, 2:11. 11. Arnsten AFT, Li BM: Neurobiology of executive functions: catecholamine 34. Sagvolden T, Wultz B, Moser EI, Moser MB, Mørkrid L: Results from a influences on prefrontal cortical functions. Biol Psychiatry 2005, comparative neuropsychological research program indicate altered 57:1377-1384. reinforcement mechanisms in children with ADD. In Attention deficit 12. Biederman J, Spencer T, Wilens T: Evidence-based pharmacotherapy for disorder: Clinical and basic research. Edited by: Sagvolden T, Archer T. attention-deficit hyperactivity disorder. Int J Neuropharmacol 2004, Hillsdale, N.J.: Lawrence Erlbaum Associates; 1989:261-286. 7:77-97. 35. Sagvolden T, Sergeant JA: Attention deficit/hyperactivity disorder–from 13. Banaschewski T, Roessner V, Dittmann RW, Santosh PJ, Rothenberger A: brain dysfunctions to behaviour. Behav Brain Res 1998, 94:1-10. Non-stimulant medications in the treatment of ADHD. Eur Child Adolesc doi:10.1186/1744-9081-7-6 Psychiatry 2004, 13:102-116. Cite this article as: Sagvolden: Impulsiveness, overactivity, and poorer 14. Grund T, Lehmann K, Bock N, Rothenberger A, Teuchert-Noodt G: Influence sustained attention improve by chronic treatment with low doses of l- of methylphenidate on brain development - an update of recent animal amphetamine in an animal model of Attention-Deficit/Hyperactivity experiments. Behav Brain Funct 2006, 2:2. Disorder (ADHD). Behavioral and Brain Functions 2011 7:6. 15. Conners CK: Forty years of methylphenidate treatment in Attention- Deficit/Hyperactivity Disorder. J Atten Disord 2002, 6(Suppl 1):S17-S30. 16. Gillberg C, Melander H, von Knorring AL, Janols LO, Thernlund G, Hagglof B, et al: Long-term stimulant treatment of children with attention-deficit hyperactivity disorder symptoms. A randomized, double-blind, placebo- controlled trial. Arch Gen Psychiatry 1997, 54:857-864. 17. Schachar R, Jadad AR, Gauld M, Boyle M, Booker L, Snider A, et al: Attention-deficit hyperactivity disorder: critical appraisal of extended treatment studies. Can J Psychiatry 2002, 47:337-348. 18. Wilens TE, Faraone SV, Biederman J, Gunawardene S: Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature. Pediatrics 2003, 111:179-185. 19. Sagvolden T: The spontaneously hypertensive rat as a model of ADHD. In Stimulant drugs and ADHD: Basic and clinical neuroscience. Edited by: Solanto MV, Arnsten AFT, Castellanos FX. New York: Oxford University Press; 2001:221-237. 20. 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, 24:31-39. 21. Sagvolden T, Russell VA, Aase H, Johansen EB, Farshbaf M: Rodent models of attention-deficit/hyperactivity disorder. Biol Psychiatry 2005, 57:1239-1247. 22. 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, 4. 23. Sagvolden T, Metzger MA, Schiørbeck 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, 58:103-112. 24. Sagvolden T: The alpha-2A adrenoceptor agonist guanfacine improves sustained attention and reduces overactivity and impulsiveness in an animal model of Attention-Deficit/Hyperactivity Disorder (ADHD). Behav Brain Funct 2006, 2:41. 25. Wultz B, Sagvolden T, Moser EI, Moser MB: The spontaneously hypertensive rat as an animal model of attention-deficit hyperactivity disorder: effects of methylphenidate on exploratory behavior. Behav Submit your next manuscript to BioMed Central Neural Biol 1990, 53:88-102. and take full advantage of: 26. Catania AC: Learning. 4 edition. N.J., Englewoods Cliffs: Prentice Hall; 1998. 27. Catania AC, Reynolds GS: A quantitative analysis of the responding • Convenient online submission maintained by interval schedules of reinforcement. J Exp Anal Behav 1968, 11(Suppl:327-Suppl):383. • Thorough peer review 28. StatSoft: Statistica for Windows. [7.1]. Tulsa, OK: StatSoft, Inc.; 2005, Ref • No space constraints or color figure charges Type: Computer Program. • Immediate publication on acceptance 29. Sleator EK, Ullman RK: Can a physician diagnose hyperactivity in the office? Pediatrics 1981, 67:13-17. • Inclusion in PubMed, CAS, Scopus and Google Scholar 30. Sagvolden T, Aase H, Zeiner P, Berger DF: Altered reinforcement • Research which is freely available for redistribution mechanisms in Attention-Deficit/Hyperactivity Disorder. Behav Brain Res 1998, 94:61-71. Submit your manuscript at www.biomedcentral.com/submit
Journal
Behavioral and Brain Functions – Springer Journals
Published: Mar 30, 2011