The irrelevancy of the inter-trial interval in delay-discounting experiments on an animal model of ADHD.

Delay discounting involves choosing between a small, immediate reward, and a larger but delayed one. As the delay between choice and large reward gets longer, people with ADHD tend to become impulsive faster than controls, indicated by a switch in preference from the large to the smaller reward. Choosing the smaller reward when the larger is considered reward maximizing is labeled impulsive behaviour. It is well documented that increased delays between choice and reward affects choice preference in both humans and other animals. Other variables such as the inter-trial interval or trial length are observed to have an effect on human discounting, but their effect on discounting in other animals is largely assumed rather than tested. In the current experiment, we tested this assumption. One group of rats was exposed to increasing delays between choosing the large reward and receiving it, while another group experienced longer inter-trial intervals that were equal in length to the delays in the other group. This ensured that trial length was controlled for in delay discounting, but that the delay function and inter-trial intervals could be manipulated and measured separately. Results showed that while the delay between choice and reward caused impulsive behaviour in rats, the length of the inter-trial interval (and by extension trial length) had no impact on choice behaviour. A follow-up experiment found this to be the case even if the length of the inter-trial interval was signaled with audio cues. These results suggest that rats, and possibly animals in general, are insensitive to time between trials, and therefore cannot easily represent human counterparts on the task.

Patterns of motor activity in spontaneously hypertensive rats compared to Wistar Kyoto rats.

BACKGROUND: Increased motor activity is a defining characteristic of patients with ADHD, and spontaneously hypertensive rats have been suggested to be an animal model of this disorder. In the present study, we wanted to use linear and non-linear methods to explore differences in motor activity patterns in SHR/NCrl rats compared to Wistar Kyoto (WKY/NHsd) rats. METHODS: A total number of 42 rats (23 SHR/NCrl and 19 WKY/NHsd, male and female) were tested. At PND 51, the animals' movements were video-recorded during an operant test procedure that lasted 90 min. Total activity level and velocity (mean and maximum), standard deviation (SD) and root mean square successive differences (RMSSD) were calculated. In addition, we used Fourier analysis, autocorrelations and two measures of complexity to characterize the time series; sample entropy and symbolic dynamics. RESULTS: The SHR/NCrl rats showed increased total activity levels in addition to increased mean and maximum velocity of movements. The variability measures, SD and RMSSD, were markedly lower in the SHR/NCrl compared to the WKY/NHsd rats. At the same time, the SHR/NCrl rats displayed a higher complexity of the time series, particularly with regard to the total activity level as evidenced by analyses of sample entropy and symbolic dynamics. Autocorrelation analyses also showed differences between the two strains. In the Fourier analysis, the SHR/NCrl rats had an increased variance in the high frequency part of the spectrum, corresponding to the time period of 9-17 s. CONCLUSION: The findings show that in addition to increased total activity and velocity of movement, the organization of behavior is different in SHR/NCrl relative to WKY/NHsd controls. Compared to controls, behavioral variability is reduced in SHR/NCrl at an aggregate level, and, concomitantly, more complex and unpredictable from moment-to-moment. These finding emphasize the importance of the measures and methods used when characterizing behavioral variability. If valid for ADHD, the results indicate that decreased behavioral variability can co-exist with increased behavioral complexity, thus representing a challenge to current theories of variability in ADHD.

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.

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.

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.

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.

Progressive ratio schedules of reinforcement.

Pigeons' pecks produced grain under progressive ratio (PR) schedules, whose response requirements increased systematically within sessions. Experiment 1 compared arithmetic (AP) and geometric (GP) progressions. Response rates increased as a function of the component ratio requirement, then decreased linearly (AP) or asymptotically (GP). Experiment 2 found the linear decrease in AP rates to be relatively independent of step size. Experiment 3 showed pausing to be controlled by the prior component length, which predicted the differences between PR and regressive ratio schedules found in Experiment 4. When the longest component ratios were signaled by different key colors, rates at moderate ratios increased, demonstrating control by forthcoming context. Models for response rate and pause duration based on Bizo and Killeen (1997) described performance on AP schedules; GP schedules required an additional parameter representing the contextual reinforcement.

A dynamic developmental theory of attention-deficit/hyperactivity disorder (ADHD) predominantly hyperactive/impulsive and combined subtypes.

Attention-deficit/hyperactivity disorder (ADHD) is currently defined as a cognitive/behavioral developmental disorder where all clinical criteria are behavioral. Inattentiveness, overactivity, and impulsiveness are presently regarded as the main clinical symptoms. The dynamic developmental behavioral theory is based on the hypothesis that altered dopaminergic function plays a pivotal role by failing to modulate nondopaminergic (primarily glutamate and GABA) signal transmission appropriately. A hypofunctioning mesolimbic dopamine branch produces altered reinforcement of behavior and deficient extinction of previously reinforced behavior. This gives rise to delay aversion, development of hyperactivity in novel situations, impulsiveness, deficient sustained attention, increased behavioral variability, and failure to "inhibit" responses ("disinhibition"). A hypofunctioning mesocortical dopamine branch will cause attention response deficiencies (deficient orienting responses, impaired saccadic eye movements, and poorer attention responses toward a target) and poor behavioral planning (poor executive functions). A hypofunctioning nigrostriatal dopamine branch will cause impaired modulation of motor functions and deficient nondeclarative habit learning and memory. These impairments will give rise to apparent developmental delay, clumsiness, neurological "soft signs," and a "failure to inhibit" responses when quick reactions are required. Hypofunctioning dopamine branches represent the main individual predispositions in the present theory. The theory predicts that behavior and symptoms in ADHD result from the interplay between individual predispositions and the surroundings. The exact ADHD symptoms at a particular time in life will vary and be influenced by factors having positive or negative effects on symptom development. Altered or deficient learning and motor functions will produce special needs for optimal parenting and societal styles. Medication will to some degree normalize the underlying dopamine dysfunction and reduce the special needs of these children. The theory describes how individual predispositions interact with these conditions to produce behavioral, emotional, and cognitive effects that can turn into relatively stable behavioral patterns.

Animal models of attention-deficit hyperactivity disorder.

Although animals cannot be used to study complex human behaviour such as language, they do have similar basic functions. In fact, human disorders that have animal models are better understood than disorders that do not. ADHD is a heterogeneous disorder. The relatively simple nervous systems of rodent models have enabled identification of neurobiological changes that underlie certain aspects of ADHD behaviour. Several animal models of ADHD suggest that the dopaminergic system is functionally impaired. Some animal models have decreased extracellular dopamine concentrations and upregulated postsynaptic dopamine D1 receptors (DRD1) while others have increased extracellular dopamine concentrations. In the latter case, dopamine pathways are suggested to be hyperactive. However, stimulus-evoked release of dopamine is often decreased in these models, which is consistent with impaired dopamine transmission. It is possible that the behavioural characteristics of ADHD result from impaired dopamine modulation of neurotransmission in cortico-striato-thalamo-cortical circuits. There is considerable evidence to suggest that the noradrenergic system is poorly controlled by hypofunctional alpha2-autoreceptors in some models, giving rise to inappropriately increased release of norepinephrine. Aspects of ADHD behaviour may result from an imbalance between increased noradrenergic and decreased dopaminergic regulation of neural circuits that involve the prefrontal cortex. Animal models of ADHD also suggest that neural circuits may be altered in the brains of children with ADHD. It is therefore of particular importance to study animal models of the disorder and not normal animals. Evidence obtained from animal models suggests that psychostimulants may not be acting on the dopamine transporter to produce the expected increase in extracellular dopamine concentration in ADHD. There is evidence to suggest that psychostimulants may decrease motor activity by increasing serotonin levels. In addition to providing unique insights into the neurobiology of ADHD, animal models are also being used to test new drugs that can be used to alleviate the symptoms of ADHD.

Behavioral effects of intra-cranial self-stimulation in an animal model of attention-deficit/hyperactivity disorder (ADHD).

Attention deficit/hyperactivity disorder (ADHD), characterized by inappropriate levels of activity, attention, and impulsivity, has been suggested to be caused by changes in reinforcement and extinction processes possibly linked to dysfunctioning dopamine systems. The present study investigated reinforcement processes in spontaneously hypertensive rats (SHR), an animal model of ADHD. Using intra-cranial self-stimulation (ICSS), behavioral effects of varying current intensity, reinforcer density, and reinforcer delay were tested. Current was varied in order to find the weakest current producing the maximal response rate (optimal current) in the SHR and the controls during high (120 reinforcers/min) and low reinforcer densities (1 reinforcer/min). The results showed that optimal current was significantly lower in the SHR than in the controls during high reinforcer density while maximal response rates were not significantly different. During low reinforcer density, optimal current was not significantly different in the two strains, but maximal response rate was significantly higher in the SHR than in the controls. The SHR produced more responses during the testing of reinforcer density, but changes in reinforcer density affected response rates similarly in the two strains. The decrease in response rate as a function of reinforcer delay was more pronounced in the SHR than in the controls. Overall, more responses with short inter-response times (IRT) were found in the SHR compared to the controls during intermittent reinforcement. The results are consistent with a steepened delay-of-reinforcement gradient in SHR.

Slower extinction of responses maintained by intra-cranial self-stimulation (ICSS) in an animal model of attention-deficit/hyperactivity disorder (ADHD).

Children with attention-deficit/hyperactivity disorder (ADHD) show performance deficits and excessive motor activity during extinction and in situations where no reinforcer can be identified, suggesting an extinction deficit in ADHD possibly linked to dopamine dysfunction. The present study examined extinction of responding previously maintained by intra-cranial self-stimulation (ICSS) in spontaneously hypertensive rats (SHR), an animal model of ADHD using three different extinction procedures. Delivery of electrical pulses were terminated altogether or presented independently of responding using two different current intensities. The results showed that more responses were retained in the SHR, especially during the initial transition from ICSS-maintained responding to response-independent delivery of electrical pulses with current reduced relative to that given during reinforcement. Slower extinction of previously reinforced behavior is suggested as an alternative explanation for the frequently observed increased behavioral output that has previously been interpreted as "disinhibition" of behavior in ADHD.

Effects of delayed reinforcers on the behavior of an animal model of attention-deficit/hyperactivity disorder (ADHD).

Attention-deficit/hyperactivity disorder (ADHD), affecting 3-5% of grade-school children, is a behavioral disorder characterized by developmentally inappropriate levels of inattention, hyperactivity, and impulsivity. It has been suggested that the symptoms are caused by altered reinforcement and extinction processes, behaviorally described as an abnormally short and steep delay-of-reinforcement gradient in ADHD. The present study tested predictions from the suggested shortened and steepened delay gradient in ADHD in an animal model, the spontaneously hypertensive rats (SHRs). It was predicted that SHR responding during baseline would mainly consist of responses with short inter-response times, and that responding would be more rapidly reduced in the SHR than in the controls by the introduction of a time interval between the response and reinforcer delivery. Effects of a resetting delay of reinforcement procedure with water as the reinforcer were tested on two baseline reinforcement schedules: variable interval 30 s (VI 30 s) and conjoint variable interval 60 s differential reinforcement of high rate 1s (VI 60 s DRH 1 s). The results showed a higher rate of responses in the SHR than in the controls during baseline, mainly consisting of responses with short inter-response times. The statistical analyses showed that response rates decreased more rapidly as a function of reinforcer delay in the SHR than in the controls. The analyses of the estimates of the reinforcer decay parameter showed no strain differences during the VI 30 s schedule but showed a significant strain difference at the end, but not at the start, of the sessions during the VI 60 s DRH 1 s schedule. In general, the results support predictions from the suggested steepened delay gradient in SHR. However, the predictions were only partly confirmed by the analyses of the decay parameter.

Rodent models of attention-deficit/hyperactivity disorder.

An ideal animal model should be similar to the disorder it models in terms of etiology, biochemistry, symptomatology, and treatment. Animal models provide several advantages over clinical research: simpler nervous systems, easily interpreted behaviors, genetic homogeneity, easily controlled environment, and a greater variety of interventions. Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder of childhood onset that is characterized by inattentiveness, hyperactivity, and impulsiveness. Its diagnosis is behaviorally based; therefore, the validation of an ADHD model must be based in behavior. An ADHD model must mimic the fundamental behavioral characteristics of ADHD (face validity), conform to a theoretical rationale for ADHD (construct validity), and predict aspects of ADHD behavior, genetics, and neurobiology previously uncharted in clinical settings (predictive validity). Spontaneously hypertensive rats (SHR) fulfill many of the validation criteria and compare well with clinical cases of ADHD. Poor performers in the five-choice serial reaction time task and Naples high-excitability rats (NHE) are useful models for attention-deficit disorder. Other animal models either focus on the less important symptom of hyperactivity and might be of limited value in ADHD research or are produced in ways that would not lead to a clinical diagnosis of ADHD in humans, even if ADHD-like behavior is displayed.

Response disinhibition may be explained as an extinction deficit in an animal model of attention-deficit/hyperactivity disorder (ADHD).

Attention-deficit/hyperactivity disorder (ADHD) is a disorder affecting between 2 and 12% of grade-school children disturbing social, academic, and occupational functioning. Problems related to social adjustment and functioning and/or psychiatric problems will exist in 50-70% of adolescents and young adults diagnosed with ADHD as children. It has been suggested that altered reinforcement and extinction processes may cause the symptoms of ADHD. The present study investigated extinction processes in spontaneously hypertensive rats (SHR), possibly the best-validated animal model of ADHD. Extinction was tested after either a variable interval (VI) or a fixed interval (FI) schedule of reinforcement with and without the presence of a conditioned reinforcer (light in the water cubicle). The results indicate a slower extinction process in the SHR compared to the normal controls, especially during the initial transition from scheduled reinforcement to extinction. Also, more responses were retained in the SHR during the later part of extinction. The extinction deficit in the SHR may be linked to reinforcer unpredictability and the presence of conditioned reinforcers, and may explain response disinhibition seen in children with ADHD.

Attention-deficit/hyperactivity disorder (ADHD) behaviour explained by dysfunctioning reinforcement and extinction processes.

Inattentiveness, overactivity and impulsiveness are presently regarded as the main clinical symptoms of attention-deficit/hyperactivity disorder (ADHD). Inattention is, however, a characteristic of most psychiatric disorders. It is argued that the ADHD Inattentive subtype may have heterogeneous origins and be qualitatively different from the ADHD Hyperactive/Impulsive subtype. At the neurobiological level, ADHD symptoms may to a large extent be caused by a dysfunctioning dopamine system: A dysfunctioning meso-limbo-cortical dopamine branch will produce altered reinforcement and extinction processes, on a behavioural level giving rise to deficient sustained attention, hyperactivity, motor and cognitive impulsiveness. A dysfunctioning nigro-striatal dopamine branch will cause 'extrapyramidal' symptoms. Our model disentangles the behaviours usually explained by 'executive functions' into cognitive impulsiveness, motor impulsiveness and deficient motor control. The various dopaminergic branches may not be equally dysfunctional in all individuals with ADHD. Etiologically, dopamine dysfunctioning will probably mainly be genetically determined while sometimes be induced by environmental factors like drugs of abuse or pollutants, which may explain geographical differences in prevalence rates.