Behavioral changes following PCB 153 exposure in the spontaneously hypertensive rat - an animal model of Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a behavioral disorder affecting 3-5% of children. Although ADHD is highly heritable, environmental factors like exposure during early development to various toxic substances like polychlorinated biphenyls (PCBs) may contribute to the prevalence. PCBs are a group of chemical industrial compounds with adverse effects on neurobiological and cognitive functioning, and may produce behavioral impairments that share significant similarities with ADHD. The present study examined the relation between exposure to PCB 153 and changes in ADHD-like behavior in an animal model of ADHD, the spontaneously hypertensive rats (SHR/NCrl), and in Wistar Kyoto (WKY/NHsd) controls. METHODS: SHR/NCrl and WKY/NHsd, males and females, were orally given PCB 153 dissolved in corn oil at around postnatal day (PND) 8, 14, and 20 at a dosage of 1, 3 or 6 mg/kg bodyweight at each exposure. The control groups were orally administered corn oil only. The animals were behaviorally tested for exposure effects from PND 37 to 64 using an operant procedure. RESULTS: Exposure to PCB 153 was associated with pronounced and long-lasting behavioral changes in SHR/NCrl. Exposure effects in the SHR/NCrl depended on dose, where 1 mg/kg tended to reduce ADHD-like behaviors and produce opposite behavioral effects compared to 3 mg/kg and 6 mg/kg, especially in the females. In the WKY/NHsd controls and for the three doses tested, PCB 153 exposure produced a few specific behavioral changes only in males. The data suggest that PCB 153 exposure interacts with strain and sex, and also indicate a non-linear dose-response relation for the behaviors observed. CONCLUSIONS: Exposure to PCB 153 seems to interact with several variables including strain, sex, dose, and time of testing. To the extent that the present findings can be generalized to humans, exposure effects of PCB 153 on ADHD behavior depends on amount of exposure, where high doses may aggravate ADHD symptoms in genetically vulnerable individuals. In normal controls, exposure may not constitute an environmental risk factor for developing the full range of ADHD symptoms, but can produce specific behavioral changes.

Marine Ο-3 polyunsaturated fatty acids induce sex-specific changes in reinforcer-controlled behaviour and neurotransmitter metabolism in a spontaneously hypertensive rat model of ADHD.

BACKGROUND: Previous reports suggest that omega-3 (n-3) polyunsaturated fatty acids (PUFA) supplements may reduce ADHD-like behaviour. Our aim was to investigate potential effects of n-3 PUFA supplementation in an animal model of ADHD. METHODS: We used spontaneously hypertensive rats (SHR). SHR dams were given n-3 PUFA (EPA and DHA)-enriched feed (n-6/n-3 of 1:2.7) during pregnancy, with their offspring continuing on this diet until sacrificed. The SHR controls and Wistar Kyoto (WKY) control rats were given control-feed (n-6/n-3 of 7:1). During postnatal days (PND) 25-50, offspring were tested for reinforcement-dependent attention, impulsivity and hyperactivity as well as spontaneous locomotion. The animals were then sacrificed at PND 55-60 and their neostriata were analysed for monoamine and amino acid neurotransmitters with high performance liquid chromatography. RESULTS: n-3 PUFA supplementation significantly enhanced reinforcement-controlled attention and reduced lever-directed hyperactivity and impulsiveness in SHR males whereas the opposite or no effects were observed in females. Analysis of neostriata from the same animals showed significantly enhanced dopamine and serotonin turnover ratios in the male SHRs, whereas female SHRs showed no change, except for an intermediate increase in serotonin catabolism. In contrast, both male and female SHRs showed n-3 PUFA-induced reduction in non-reinforced spontaneous locomotion, and sex-independent changes in glycine levels and glutamate turnover. CONCLUSIONS: Feeding n-3 PUFAs to the ADHD model rats induced sex-specific changes in reinforcement-motivated behaviour and a sex-independent change in non-reinforcement-associated behaviour, which correlated with changes in presynaptic striatal monoamine and amino acid signalling, respectively. Thus, dietary n-3 PUFAs may partly ameliorate ADHD-like behaviour by reinforcement-induced mechanisms in males and partly via reinforcement-insensitive mechanisms in both sexes.

Differential expression of SLC9A9 and interacting molecules in the hippocampus of rat models for attention deficit/hyperactivity disorder.

SLC9A9 [solute carrier family 9, member 9, also known as Na(+)/H(+) exchanger member 9 (NHE9)], has been implicated in human attention deficit/hyperactivity disorder (ADHD), autism, and rat studies of hyperactivity and inattentiveness. SLC9A9 is a membrane protein that regulates the luminal pH of the recycling endosome. We recently reported the interactions of SLC9A9 with two molecules: calcineurin homologous protein (CHP) and receptor for activated C-kinase 1 (RACK1). We also reported two novel SLC9A9 mutations and abnormal gene expression profiles in the brains of an inattentive type rat model of ADHD (WKY/NCrl rat). In this study, we further examined the expression and relationship of SLC9A9 and 9 additional genes (CHP, RACK1, CaM, PPP3R1, PPP1R10, PKCm, CaMKI, NR2B, PLCb1) that may directly or indirectly interact with SLC9A9 in the hippocampus of the WKY/NCrl rat and the spontaneously hypertensive rat (SHR) model of the combined type of ADHD. We found that the expression levels of these genes were significantly correlated, suggesting that they may be coregulated. Principal component analysis identified two main factors that accounted for 94% of the expression variance of the 10 genes. Significant differences were found for both factors across the 3 different rat strains. The two ADHD rat models (WKY/NCrl and SHR), although different from each other in adulthood, showed similar profiles in adolescence. Both models were significantly different from WKY/NHsd control rats at both ages. The expression abnormalities of each gene were evaluated and their roles in cell signaling processes such as calcium signaling and protein phosphorylation are discussed. Our results suggest that abnormalities in SLC9A9-mediated signaling pathways could contribute to the ADHD phenotype of two rat models (WKY/NCrl and SHR/NCrl), and that the perturbation of the SLC9A9 network is age-dependent.

The four causes of ADHD: a framework.

In addition to the symptoms singled out by the diagnostic criteria for Attention-Deficit Hyperactivity Disorder (ADHD), a comprehensive definition should inform us of the events that trigger ADHD in both its acute and chronic manifestations; the neurobiology that underlies it; and the evolutionary forces that have kept it in the germ line of our species. These factors are organized in terms of Aristotle's four kinds of "causes," or explanations: formal, efficient, material, and final. This framework systematizes the nosology, biology, psychology, and evolutionary pressures that cause ADHD.

Rat models of ADHD.

Showing that an animal is hyperactive is not sufficient for it to be accepted as a model of ADHD. Based on behavioral, genetic, and neurobiological data, the spontaneously hypertensive rat (SHR) obtained from Charles River, Germany, (SHR/NCrl) is at present the best-validated animal model of ADHD. One Wistar Kyoto substrain (WKY/NHsd), obtained from Harlan, UK, is its most appropriate control. Another WKY substrain (WKY/NCrl) obtained from Charles River, Germany, is inattentive, has distinctly different genetics and neurobiology, and provides a promising model for the predominantly inattentive subtype of ADHD (ADHD-I) if one wants to investigate categorical ADHD subtypes. In this case, also, the WKY/NHsd substrain should be used as control. Although other rat strains may behave like WKY/NHsd rats, neurobiological results indicate significant differences when compared to the WKY/NHsd substrain, making them less suitable as controls for the SHR/NCrl. Thus, there are no obvious behavioral differences among the various SHRs, but there are behavioral and neurobiological differences among the WKY strains. The use of WKY/NCrl, outbred Wistar, Sprague Dawley, or other rat strains as controls for SHR/NCrl may produce spurious neurobiological effects and erroneous conclusions. Finally, model data yield support to independent hyperactivity and inattention dimensions in ADHD behavior.

SLC9A9 mutations, gene expression, and protein-protein interactions in rat models of attention-deficit/hyperactivity disorder.

SLC9A9 (solute carrier family 9, member 9, also known as Na+/H+ exchanger member (NHE9)) is a membrane protein that regulates the luminal pH of the recycling endosome, an essential organelle for synaptic transmission and plasticity. SLC9A9 has been implicated in human attention deficit hyperactivity disorder (ADHD) and in rat studies of hyperactivity. We examined the SLC9A9 gene sequence and expression profile in prefrontal cortex, dorsal striatum and hippocampus in two genetic rat models of ADHD. We report two mutations in a rat model of inattentive ADHD, the WKY/NCrl rat, which affect the interaction of SLC9A9 with calcineurin homologous protein (CHP). We observed an age-dependent abnormal expression of SLC9A9 in brains of this inattentive model and in the Spontaneous Hypertensive Rat (SHR) model of ADHD. Our data suggest a novel mechanism whereby SLC9A9 sequence variants and abnormalities in gene expression could contribute to the ADHD-like symptoms of rat models and possibly the pathophysiology of ADHD in humans.

Postnatal exposure to PCB 153 and PCB 180, but not to PCB 52, produces changes in activity level and stimulus control in outbred male Wistar Kyoto rats.

BACKGROUND: Polychlorinated biphenyls (PCBs) are a class of organic compounds that bioaccumulate due to their chemical stability and lipophilic properties. Humans are prenatally exposed via trans-placental transfer, through breast milk as infants, and through fish, seafood and fatty foods as adolescents and adults. Exposure has several reported effects ranging from developmental abnormalities to cognitive and motor deficiencies. In the present study, three experimental groups of rats were orally exposed to PCBs typically found in human breast milk and then behaviorally tested for changes in measures of stimulus control (percentage lever-presses on the reinforcer-producing lever), activity level (responses with IRTs > 0.67 s), and responses with short IRTs (< 0.67 s). METHODS: Male offspring from Wistar Kyoto (WKY/NTac) dams purchased pregnant from Taconic Farms (Germantown, NY) were orally given PCB at around postnatal day 8, 14, and 20 at a dose of 10 mg/kg body weight at each exposure. Three experimental groups were exposed either to PCB 52, PCB 153, or PCB 180. A fourth group fed corn oil only served as controls. From postnatal day 25, for 33 days, the animals were tested for behavioral changes using an operant procedure. RESULTS: PCB exposure did not produce behavioral changes during training when responding was frequently reinforced using a variable interval 3 s schedule. When correct responses were reinforced on a variable interval 180 s schedule, animals exposed to PCB 153 or PCB 180 were less active than controls and animals exposed to PCB 52. Stimulus control was better in animals exposed to PCB 180 than in controls and in the PCB 52 group. Also, the PCB 153 and PCB 180 groups had fewer responses with short IRTs than the PCB 52 group. No effects of exposure to PCB 52 were found when compared to controls. CONCLUSIONS: Exposure to PCBs 153 and 180 produced hypoactivity that continued at least five weeks after the last exposure. No effects of exposure to PCB 52 were observed.

Impulsiveness, overactivity, and poorer sustained attention improve by chronic treatment with low doses of l-amphetamine in an animal model of Attention-Deficit/Hyperactivity Disorder (ADHD).

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.

Intraindividual variability (IIV) in an animal model of ADHD - the Spontaneously Hypertensive Rat.

Attention-deficit/hyperactivity disorder (ADHD) is characterized by numerous behaviors including inattention, hyperactivity and impulsiveness. ADHD-affected individuals also have high intra-individual variability (IIV) in reaction time. The genetic control of IIV is not well understood. The single study of the genetics of this phenomenon in humans detected only marginal associations between genotypes at two candidate genes for ADHD and variability in response time. The Spontaneously Hypertensive Rat (SHR/NCrl) is an animal model of ADHD, expressing high activity, inattention and impulsive behavior during operant and task tests. The SHR might be useful for identifying genes for variability, but it is not known whether it also expresses high IIV, as is symptomatic of ADHD. We therefore conducted an investigation of IIV in the SHR. We used 16 SHR/NCrl rats and 15 Wistar-Kyoto (WKY/Nico) controls applying a reinforcement schedule used in the validation of the SHR as an animal model of ADHD. We represented IIV as the average absolute deviation of individual behavior within the five 18-min segments of each experimental session from the average behavioral trait value within that session ('individual phenotypic dispersion', PDi). PDi for hyperactivity, impulsiveness and inattention in the SHR and WKY rats was analyzed using nonparametric ranking by experimental session. SHR/NCrl rats had higher PDi than WKY/Nico controls for impulsiveness and inattention. There was a significant upward trend for PDi over experimental segments within sessions for attention in SHR rats, but not in WKY. PDi for hyperactivity was correlated with PDi for impulsiveness and we therefore excluded observations associated with short IRTs (< 0.67 s); dispersion in hyperactivity outside this interval was also significantly higher in SHR rats than in WKY rats. Some studies indicate the sharing of symptoms of hyperactivity and impulsiveness in SHR and ADHD-affected humans; high IIV in operant behavioral metrics suggests that the SHR may be useful in elucidating the genetic basis for IIV in humans.

The spontaneously hypertensive rat model of ADHD--the importance of selecting the appropriate reference strain.

Although several molecular and genetic manipulations may produce hyperactive animals, hyperactivity alone is insufficient for the animal to qualify as a model of ADHD. Based on a wider range of criteria - behavioral, genetic and neurobiological - the spontaneously hypertensive rat (SHR) obtained from Charles River, Germany (SHR/NCrl) at present constitutes the best validated animal model of ADHD combined subtype (ADHD-C), and the Wistar Kyoto substrain obtained from Harlan, UK (WKY/NHsd) is its most appropriate control. Although other rat strains may behave like WKY/NHsd rats, genetic results indicate significant differences when compared to the WKY/NHsd substrain, making them less suitable controls for the SHR/NCrl. The use of WKY/NCrl, outbred Wistar, Sprague Dawley or other rat strains as controls for SHRs may produce spurious neurobiological differences. Consequently, data may be misinterpreted if insufficient care is taken in the selection of the control group. It appears likely that the use of different control strains may underlie some of the discrepancies in results and interpretations in studies involving the SHR and WKY. Finally, we argue that WKY rats obtained from Charles River, Germany (WKY/NCrl) provide a promising model for the predominantly inattentive subtype of ADHD (ADHD-PI); in this case also the WKY/NHsd substrain should be used as control.

Origins of altered reinforcement effects in ADHD.

Attention-deficit/hyperactivity disorder (ADHD), characterized by hyperactivity, impulsiveness and deficient sustained attention, is one of the most common and persistent behavioral disorders of childhood. ADHD is associated with catecholamine dysfunction. The catecholamines are important for response selection and memory formation, and dopamine in particular is important for reinforcement of successful behavior. The convergence of dopaminergic mesolimbic and glutamatergic corticostriatal synapses upon individual neostriatal neurons provides a favorable substrate for a three-factor synaptic modification rule underlying acquisition of associations between stimuli in a particular context, responses, and reinforcers. The change in associative strength as a function of delay between key stimuli or responses, and reinforcement, is known as the delay of reinforcement gradient. The gradient is altered by vicissitudes of attention, intrusions of irrelevant events, lapses of memory, and fluctuations in dopamine function. Theoretical and experimental analyses of these moderating factors will help to determine just how reinforcement processes are altered in ADHD. Such analyses can only help to improve treatment strategies for ADHD.

The neuroscience peer review consortium.

The Neuroscience Peer Review Consortium (NPRC) was conceived in the summer of 2007 at a meeting of editors and publishers of neuroscience journals. One of the working groups addressed whether it was possible to construct a system for permitting authors whose manuscript received supportive reviews at one journal but was not accepted to send a revised manuscript together with its first round of reviews to a new journal for the second round. This would speed up the review process and reduce the work for reviewers and editors. The working group not only designed a framework for transferring reviews among journals, but also implemented it as the NPRC. By the fall of 2007, more than a dozen major journals had signed onto the NPRC, sufficient to launch the experiment in January, 2008. We invite authors who have not yet used the NPRC to try this method for appropriate manuscripts.In order to encourage dissemination of the details outlined in this Editorial, it will also be published in other journals in the Neuroscience Peer Review Consortium.

Dynamic behavioural changes in the Spontaneously Hyperactive Rat: 3. Control by reinforcer rate changes and predictability.

Variable intervals are widely believed to produce steady rates of responding. However, based on the calming effect of unpredictability in attention deficit hyperactivity disorder (ADHD) we hypothesised that an animal model of this disorder, the Spontaneously Hyperactive (or Hypertensive) Rat, would become less active following particularly variable sequences of interval-lengths in a variable interval schedule. From a large dataset of holepokes and tray-reports by rats in a variable interval reinforcement schedule, we extracted numerous short sequences of intervals on the basis of the first, second, and third derivatives of reinforcement timing (i.e. rate, acceleration, and jerk) in recent intervals. Sets of selected intervals were compared with one another to elucidate the effect of these different derivatives on behaviour in the current interval. Results show that SHR are more active after richer recent reinforcement; after decelerating reinforcers; and after predictable reinforcers. The hypothesis is supported. In conclusion, SHR behaviour largely complies with the Extended Temporal Difference model which in turn has been previously validated against published data in ADHD. The Extended TD model therefore is able to account for two species' behaviour in a wide range of experimental paradigms. SHR are similar in several respects to group averages of children with ADHD, except that SHR have reduced variability and perform actions faster than controls. Hyperactivity in the SHR is very dependent on momentary environmentally determined states, which is an important area for future investigation of ADHD.

Dynamic behavioural changes in the Spontaneously Hyperactive Rat: 1. Control by place, timing, and reinforcement rate.

Several existing theoretical models of Attention Deficit Hyperactivity Disorder (ADHD) predict that a high or low learning rate contributes to some cases of ADHD; and that this is controlled by the dopamine signal. The Spontaneously Hypertensive (Hyperactive) Rat has an abnormal Dopamine Transporter (DAT), which is likely to be hypofunctional, thereby increasing the dopamine concentration and the learning rate. We therefore test the prediction that the SHR learns too fast. Using a variable interval reinforcement schedule, we looked for increased responding within each interval, at around the durations of the last three intervals. At the time predicted by the previous interval, SHR responded significantly (10%) more than their baseline rate, and control WKY rats similarly less than their baseline. At the time predicted by the second (and third) previous intervals, there were minor trends (and no change) in the same direction. In summary, at the times predicted, SHR respond more than control rats. The effect size is insufficient to account for all the differences from control rats, such as their nearly threefold greater operant responding. At the times when SHR increase responding, WKY suppress it. This demonstrates similar learning to the SHR but the opposite response, probably due to anxiety about the bang accompanying reinforcer delivery: WKY are known to have a very negative response to stress. Interval schedules with randomised interval lengths have considerable potential for assessing multiple causes of behaviour, particularly those acting over short timecourses. Alterations in learning rate are not a sufficient explanation for either SHR or ADHD difference from controls.

Dynamic behavioural changes in the Spontaneously Hyperactive Rat: 2. Control by novelty.

An important aspect of attention deficit hyperactivity disorder (ADHD) is its temporary amelioration by novelty and by stimulant medication. Extant learning-based accounts of ADHD are unable to account for the temporary amelioration effect. One possible mechanism is a drive for novelty. Computational simulations have previously shown that such a drive can result from a "dopamine appetite". Empirical demonstration of such a process requires, as a first step, the development of standard criteria for identifying drive-based, versus learning-based, changes in behaviour. Using a variable-interval reinforcement schedule, we looked over a range of timescales for behavioural changes showing putative characteristics of drives, namely: low information content, unidirectionality, saturability, spontaneous reversibility in less than a day, and cycle stability. SHR lacks normal down-regulation of responding when the schedule becomes sparser. SHR appears to be re-learning the schedule length during the days of each calendar week. SHR hyperactivity is specific to the operant and develops gradually over the first five minutes of each session. Empirical within-session results were replicated by a simple simulation containing two interacting reward systems, one for water and the other for stimulation (including novelty). To summarise, enhanced sensation-seeking (or a subtype of it, novelty-seeking) provides the best available account of changes in SHR activity within sessions, though not of changes over longer timecourses. Sensation-seeking appears to be associated with low anxiety in the SHR. SHR propensity to display multiple influences on their behaviour makes them ideal for further pharmacological, genetic, and behavioural investigation.

A comparison of molecular alterations in environmental and genetic rat models of ADHD: a pilot study.

Attention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral disorder in school-aged children. In addition to genetic factors, environmental influences or gene x environmental interactions also play an important role in ADHD. One example of a well studied environmental risk factor for ADHD is exposure to polychlorinated biphenyls (PCBs). In this study, we investigated whether the well-established genetic model of ADHD based on the spontaneously hypertensive rat (SHR) and a well established PCB-based model of ADHD exhibited similar molecular changes in brain circuits involved in ADHD. The brains from 28 male rats (8 SHR, 8 Sprague-Dawley (SD) controls, 8 Wistar/Kyoto (WKY) controls, and 4 PCB-exposed SD rats) were harvested at postnatal days (PNDs) 55-65 and RNA was isolated from six brain regions of interest. The RNA was analyzed for differences in expression of a set of 308 probe sets interrogating 218 unique genes considered highly relevant to ADHD or epigenetic gene regulation using the Rat RAE230 2.0 GeneChip (Affymetrix). Selected observations were confirmed by real-time quantitative RT-PCR. The results show that the expression levels of genes Gnal, COMT, Adrbk1, Ntrk2, Hk1, Syt11, and Csnk1a1 were altered in both the SHR rats and the PCB-exposed SD rats. Arrb2, Stx12, Aqp6, Syt1, Ddc, and Pgk1 expression levels were changed only in the PCB-exposed SD rats. Genes with altered expression only in the SHRs included Oprm1, Calcyon, Calmodulin, Lhx1, and Hes6. The epigenetic genes Crebbp, Mecp2, and Hdac5 are significantly altered in both models. The data provide strong evidence that genes and environment can affect different set of genes in two different models of ADHD and yet result in the similar disease-like symptoms.

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).

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. While dopamine release is decreased in SHR, norepinephrine concentrations are elevated. The primary objective of the present research was to test effects of a range of doses of the catecholamine agonists d- and l-amphetamine on ADHD-like symptoms in SHR. METHODS: The present study tested behavioral effects of 0.64 to 1.91 mg/kg d-amphetamine; and 1.27 to 3.81 mg/kg 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 during baseline conditions in the SHR were improved by treatment with the amphetamine isomers. The dose-response curves were, however, different for the different behaviors. Most significantly, d-amphetamine reduced overactivity and impulsiveness more efficiently than comparable doses of l-amphetamine. The lowest dose of d-amphetamine and low-to-medium doses of l-amphetamine improved sustained attention. The highest dose of d-amphetamine used interfered with SHR behavior. A second study showed that the impaired sustained attention (percent correct lever choice) in the SHR was not due to impaired visual functions or poorer working memory. DISCUSSION: The present results indicate that overactivity and impulsiveness may to some extent be associated with imbalances in neural circuits that differ from those causing poor sustained attention and that the two amphetamine isomers may affect the different neuromodulators differently. While d-amphetamine improved SHR overactivity, impulsiveness as well as sustained attention, the behavioral effects of l-amphetamine were relatively more specific for improving sustained attention than for the other 2 symptoms. Thus, while d- and l-amphetamine affect similar neuronal systems their relative potencies may be different.

Behavioral variability, elimination of responses, and delay-of-reinforcement gradients in SHR and WKY rats.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is characterized by a pattern of inattention, hyperactivity, and impulsivity that is cross-situational, persistent, and produces social and academic impairment. Research has shown that reinforcement processes are altered in ADHD. The dynamic developmental theory has suggested that a steepened delay-of-reinforcement gradient and deficient extinction of behavior produce behavioral symptoms of ADHD and increased behavioral variability. METHOD: The present study investigated behavioral variability and elimination of non-target responses during acquisition in an animal model of ADHD, the spontaneously hypertensive rat (SHR), using Wistar Kyoto (WKY) rats as controls. The study also aimed at providing a novel approach to measuring delay-of-reinforcement gradients in the SHR and the WKY strains. The animals were tested in a modified operant chamber presenting 20 response alternatives. Nose pokes in a target hole produced water according to fixed interval (FI) schedules of reinforcement, while nose pokes in the remaining 19 holes either had no consequences or produced a sound or a short flickering of the houselight. The stimulus-producing holes were included to test whether light and sound act as sensory reinforcers in SHR.Data from the first six sessions testing FI 1 s were used for calculation of the initial distribution of responses. Additionally, Euclidean distance (measured from the center of each hole to the center of the target hole) and entropy (a measure of variability) were also calculated.Delay-of-reinforcement gradients were calculated across sessions by dividing the fixed interval into epochs and determining how much reinforcement of responses in one epoch contributed to responding in the next interval. RESULTS: Over the initial six sessions, behavior became clustered around the target hole. There was greater initial variability in SHR behavior, and slower elimination of inefficient responses compared to the WKY. There was little or no differential use of the stimulus-producing holes by either strain. For SHR, the reach of reinforcement (the delay-of-reinforcement gradient) was restricted to the preceding one second, whereas for WKY it extended about four times as far. CONCLUSION: The present findings support previous studies showing increased behavioral variability in SHR relative to WKY controls. A possibly related phenomenon may be the slowed elimination of non-operant nose pokes in SHR observed in the present study. The findings provide support for a steepened delay-of-reinforcement gradient in SHR as suggested in the dynamic developmental theory of ADHD. Altered reinforcement processes characterized by a steeper and shorter delay-of-reinforcement gradient may define an ADHD endophenotype.

The alpha-2A adrenoceptor agonist guanfacine improves sustained attention and reduces overactivity and impulsiveness in an animal model of Attention-Deficit/Hyperactivity Disorder (ADHD).

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. While dopamine release is decreased in SHR prefrontal cortex, norepinephrine concentrations are elevated. The noradrenergic system appears to be hyperactive as a result of impaired alpha-2A adrenoceptor regulation. Thus, the present study tested behavioral effects of the centrally acting alpha-2A adrenoceptor agonist guanfacine on SHR behavior. METHODS: The present study tested behavioral effects of guanfacine at doses of 0.075, 0.15, 0.30 and 0.60 mg base/kg i.p. in both 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 reduced sustained attention during baseline conditions in the SHR improved by treatment with guanfacine. The most pronounced improvement in SHR behavior was seen following the two highest doses (0.3 and 0.6 mg/kg) of guanfacine when SHR behaviors virtually normalized. The positive effects of the drug were most marked towards the end of the session. CONCLUSION: The results indicate that guanfacine improved poor noradrenergic modulation of neuronal circuits that involve the frontal lobes in an animal model of ADHD. The present results support the beneficial effects of guanfacine on ADHD behavior reported clinically and experimentally in primate models of frontal function. It is likely that guanfacine improved prefrontal functions in the SHR. It cannot be concluded, however, that the effects of the drug are mediated solely by norepinephrine.

Fine motor skills in South African children with symptoms of ADHD: influence of subtype, gender, age, and hand dominance.

BACKGROUND: Motor problems, often characterised as clumsiness or poor motor coordination, have been associated with ADHD in addition to the main symptom groups of inattention, impulsiveness, and overactivity. The problems addressed in this study were: (1) Are motor problems associated with ADHD symptoms, also in African cultures? (2) Are there differences in motor skills among the subtypes with ADHD symptoms? (3) Are there gender differences? (4) Is there an effect of age? (5) Are there differences in performance between the dominant and non-dominant hand? METHOD: A total of 528 children (264 classified as having symptoms of ADHD and 264 matched comparisons) of both genders and from seven different South African ethnic groups participated in the study. They were assessed with three simple, easy to administer instruments which measure various functions of motor speed and eye-hand coordination: The Grooved Pegboard, the Maze Coordination Task, and the Finger Tapping Test. The results were analysed as a function of subtype, gender, age, and hand dominance. RESULTS: The findings indicate that children with symptoms of ADHD performed significantly poorer on the Grooved Pegboard and Motor Coordination Task, but not on the Finger Tapping Test than their comparisons without ADHD symptoms. The impairment was most severe for the subtype with symptoms of ADHD-C (combined) and less severe for the subtypes with symptoms of ADHD-PI (predominantly inattentive) and ADHD-HI (predominantly hyperactive/impulsive). With few exceptions, both genders were equally affected while there were only slight differences in performance between the dominant and non-dominant hand. The deficiencies in motor control were mainly confined to the younger age group (6-9 yr). CONCLUSION: An association between the symptoms of ADHD and motor problems was demonstrated in terms of accuracy and speed in fairly complex tasks, but not in simple motor tests of speed. This deficiency is found mainly in the children with ADHD-C symptoms, but also to a lesser degree in the children with symptoms of ADHD-PI and ADHD-HI.