[1] 5w Rodent Models of Attention-Deficit/Hyperactivity Disorder

[1] 200w 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.

[1] 75w Genetics. Attention-deficit/hyperactivity disorder is a genetic disorder, most likely caused by multiple genes with small effect size (Sagvolden et al, in press). Optimal animal models should therefore be neurodevelopmental, preferably genetic models. Genetic studies link ADHD to the human dopamine receptor 4 gene (DRD4) mapped to chromosome 11p15.5 (Cook et al 1995) and allelic variations of the gene for the plasma-membrane dopamine transporter (DAT-1) (Kuntsi and Stevenson 2000), which is responsible for synaptic dopamine uptake.

[2] 44w Neuropathology. In addition to behavioral criteria, an animal model should display the structural and functional neuropathology of ADHD (i.e., reduced frontal lobe activity, increased somatosensory cortical blood flow, abnormal caudate, and reduced brain volumes; Castellanos et al 2002;Lou et al 1989;Paule et al 2000).

[3] 51w Neurotransmitter Dysfunction. A role for dysfunction of dopamine and other monoamine systems in ADHD has been suspected because the most effective drugs used to treat ADHD are psychostimulants that block dopamine and norepinephrine transporters. Animal models should have similar neurotransmitter dysfunction and provide insight into the neural disturbances of the disorder.

[4] 128w Delay-of-Reinforcement Gradient. Reinforcers act retroactively on past responses by increasing the probability of future responses of the same operant class (Catania et al 1988). The reinforcing effect is largest when the reinforcer is delivered immediately after the response and wanes when reinforcer delivery is delayed (Figure 1). This relationship between the effect of the reinforcer and the interval between response and reinforcer is called the "delay-of-reinforcement gradient" or the "delay gradient" (Catania et al 1988;Johansen et al 2002;Sagvolden et al, in press). I t h a s been argued that ADHD symptoms are caused by steeper and shorter delay gradients and slower extinction of previously reinforced behavior (Johansen et al 2002;Sagvolden et al, in press). The behavior of animal models should be consistent with a steeper delay gradient.

[5] 101w Motor Impulsiveness. Not only single responses (e.g., R C in Figure 1), but also the relationships between responses (e.g., IRTs; see Figure 1, right panel) are conditioned and maintained by reinforcers (Catania 1971;Catania et al 1988;Sagvolden et al 1998). In contrast to the normal delay gradient, the steeper delay gradient of children with ADHD is too short to reinforce the long IRT involved in the sequence R D -R C , (Figure 1, right panel). This reinforcement process explains why motor impulsiveness, responses emitted with short IRTs, is not present in a novel situation but develops gradually (Sagvolden et al 1998).

[6] 58w Impaired Sustained Attention. The three-term contingencystimulus-response-consequence relationship (Catania 1998)-is important to understand the impaired sustained attention in ADHD. When reinforcers are infrequent, the short delay gradient might prevent an association being formed between the discriminative stimulus and the reinforcement contingency, resulting in poorer stimulus control and possibly impaired sustained attention as in ADHD (Sagvolden et al, in press).

[7] 194w Hyperactivity. Response selection is a function of reinforcement and extinction. Hyperactivity in ADHD might be due to a combination of the steeper and shorter delay gradient and deficient extinction (Sagvolden et al, in press). Both factors are probably rooted in genetically based hypofunctional dopamine systems. The effect of a reinforcer is more potent when the delay between the response and the reinforcer is short than when the delay is long. If the delay gradient is steeper and shorter in children with ADHD, then delayed reinforcers will have little effect on the behavior of children with ADHD. Furthermore, it is predicted that the extinction process is faulty in ADHD. This means that the normal elimination, in particular, of previously established but no longer reinforced responses, will take place to a lesser extent than normal in children with ADHD. Thus, altered reinforcement processes characterized by a steeper and shorter delay gradient in ADHD will not by itself generate the gradually developing hyperactivity. Overactivity might be acquired and maintained by a combination of scheduled and unscheduled reinforcers and failing extinction, increasing the frequency of acquired responses without pruning ineffective and inadequate responses (Sagvolden et al, in press).

[8] 63w Motor Control Problems. The neostriatum is central to integrating motor output and receives the greatest density of dopamine of all central nervous structures. Striatal dopamine hypofunction might be associated with subtle motor control problems, neurologic "soft signs," in children with ADHD (Sagvolden et al, in press). Neostriatal hypofunctioning might contribute to the poor motor development associated with severe cases of ADHD (Taylor 1998).

[9] 40w Psychostimulant Effects. Psychostimulant drugs increase synaptic dopamine availability and enhance the effects of reinforcers (Sagvolden et al, in press;Volkow et al 2002). Psychomotor stimulant drugs should have the same effects in animal models as in children and adults with ADHD.

[10] 73w Conclusion. It will be difficult to conclude on the construct validity of an animal model because of limited agreement on the theoretical rationale for ADHD. The theory proposed by Sagvolden et al (in press) suggests that there are two main behavioral processes that cause ADHD: altered reinforcement of novel behavior and deficient extinction of previously reinforced behavior. Similar alterations in behavior, genetics, and neurobiology should be found in an animal model for ADHD.

[1] 104w It is premature to conclude on the construct validity of the SHR as an ADHD model because of limited agreement on the theoretical rationale for ADHD. Results obtained with SHR are consistent with the key behavioral processes suggested to cause ADHD: altered reinforcement of novel behavior and deficient extinction of previously reinforced behavior. These processes are likely to be associated with hypofunction of the mesolimbic and other dopamine systems, such as the mesocortical dopamine system associated with deficient attention responses and poor behavioral organization and the nigrostriatal dopamine system that impairs motor functions and causes poor nondeclarative habit learning (Sagvolden et al, in press).

[2] 225w Although several investigators have argued that altered reinforcement processes are important in ADHD symptomatology, details of these processes and their consequences were not known before the availability of SHR as an animal model (Sagvolden 2000;Sagvolden et al, in press). The most striking predictions are currently found on the behavioral level in terms of more precise descriptions of the altered delay gradient and resulting predictions of motor impulsiveness as the development of an overabundance of responses with short IRTs, development of hyperactivity, and nature of sustained attention in ADHD as discussed in the previous sections. The usefulness of the SHR as an animal model of ADHD might become apparent in the future not only in behavior but also in genetics, neurobiology, and pharmacology. Operant analysis of behavior has turned out to be the "electron microscope" of behavioral science by yielding a lot of valuable new data in the validation of the SHR as an animal model of ADHD. There is reason to believe that the model will continue to reveal hitherto unknown aspects of ADHD behavior. In addition, further genetic studies might help localize candidate genes. The very sensitive neurobiological methods available in the animal laboratory might help point out exactly which brain structures are malfunctioning in ADHD children (Carey et al 1998;Papa et al 1998). Finally, the model might be used for testing new drugs.

[3] 37w Limitations. Hypertension is a confounding factor in the SHR model of ADHD; however, because hypertension develops later in life and is not present in young hyperactive SHR, it is advisable to study prehypertensive, prepubertal 4-to 5-week-old SHR.

[4] 38w Strict criteria have introduced objectivity to the study of animal models of ADD and ADHD; however, it is impossible to completely fulfill the requirements for assessing the validity of animal models because of the inadequate understanding of ADHD.

[5] 77w Of all the animal models that have been proposed, the SHR best fits the criteria for ADHD, whereas NHE rat and poor 5-CSRT performers promise to be useful models for ADD. 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 (Table 1).

[1] 147w Optimal animal models should be similar to clinical cases in terms of etiology, biochemistry, symptomatology, and treatment (McKinney and Bunney 1969). Models usually have simpler nervous systems, and their behaviors are easier to interpret than clinical cases. Additionally, models are often more genetically homogeneous, their environment is easy to control, and more interventions are possible than in clinical cases. Sarter et al (1992) developed validation criteria for animal models of human disorders. Recently, criteria for assessing models for ADD and ADHD were proposed (Sagvolden 2000). An ADHD model must conform to three validation criteria: face validity, construct validity, and predictive validity. Face validity is the ability to fundamentally mimic the behavioral clinical characteristics of the disorder. Construct validity conforms to a theoretical rationale for the disorder. Predictive validity is the ability to predict previously unknown aspects of behavior, genetics, and neurobiology of the disorder from the model.

[2] 66w Face and predictive validity represent the empirical status of a model, whereas construct validity represents the model's theoretical status (Willner 1986). A model can be valid if some face or predictive validities are not met, although it cannot be valid if construct validity is violated; this is problematic in poorly understood disorders such as ADD and ADHD. Nonetheless, data from all validity criteria should be considered.

[3] 130w ADHD can be demonstrated with multiple fixed-interval/extinction schedules of reinforcement (FI/Ext schedules) with two or more components that operate in alternation, each in the presence of a different stimulus (Sagvolden et al 1998). The fixedinterval component delivers reinforcers at fixed time intervals when the required response is performed (e.g., a lever is pressed). The efficacy of the reinforcer (the delay-of-reinforcement gradient, Figure 1) and the maximum attainable response rate are measured (Sagvolden et al 1992b(Sagvolden et al , 1993)). The schedule also enables measurements of motor impulsiveness, that is, premature responses. In this particular case, impulsiveness is measured as responses with short interresponse times (IRTs). The extinction component measures sensitivity to stimulus change and the ability to sustain attention. When the extinction component is in effect, no reinforcer is delivered.

[4] 88w Motor Impulsiveness. Impulsiveness might be the most significant ADHD symptom (Johansen et al 2002;Sagvolden and Sergeant 1998;Taylor 1998). Motor impulsiveness is operationalized as bursts of responses with short IRTs (Johansen et al 2002;Sagvolden et al, in press). This response pattern is inefficient in FI/Ext schedules because the behavior does not result in an increased number of reinforcers. Children with ADHD do not exhibit motor impulsiveness in novel situations; impulsiveness develops gradually over time (Sagvolden et al 1998). This is an important criterion for any animal model of ADHD.

[5] 97w Deficient Sustained Attention. In clinical settings, sustained attention deficit occurs when stimuli are widely spaced in time (van der Meere 1996) or the task is unwelcome or uninteresting (Taylor 1998). In the extinction component of FI/Ext schedules, children with ADHD had normal sustained attention at initiation of testing, but it markedly decreased with repeated testing over time. Furthermore, at the start of every extinction component, both ADHD and normal children noticed the onset of the extinction component (a light signal) and stopped responding, but children with ADHD resumed responding after a short time (Sagvolden et al 1998).

[6] 50w Hyperactivity. Hyperactivity, like impulsiveness, is absent in novel situations, including test initiation (Sagvolden et al 1998;Sleator and Ullmann 1981). In FI/Ext schedules, children with and without ADHD had similar activity levels at initiation of testing. Hyperactivity developed gradually in children with ADHD as the test proceeded (Sagvolden et al 1998).

[7] 58w Conclusion. The optimal animal model for ADHD should ideally mimic ADHD in all respects: 1) impulsiveness should be absent initially and develop gradually over time; 2) sustained attention-deficit should be demonstrated only when stimuli are widely spaced in time; and 3) like ADHD children, the model should not display hyperactivity in a novel environmenthyperactivity should develop over time.

[8] 31w The spontaneously hypertensive rat (SHR) is the most frequently used model of ADHD (Sagvolden 2000). It is a genetic model bred from progenitor Wistar Kyoto rats (WKY) (Okamoto and Aoki 1963).

[9] 37w Face Validity. The design of comparative behavioral tests used with animal models is based on operant analyses of behavior developed by Skinner (Ferster and Skinner 1957). These studies are easy to replicate and make comparative research possible.

[10] 54w Behavioral characteristics of SHR were investigated with the multiple FI/Ext schedules used for ADHD children, with the same computer programs and type of interface, but different manipulanda and reinforcers (trinkets for children, water droplets for rats; Sagvolden 2000). Similar results were obtained for SHR and ADHD children (Sagvolden 2000;Sagvolden et al 1998) (Figure 2).

[11] 79w Motor Impulsiveness. As in ADHD, impulsiveness in SHR presents as brief sequences of activity and rapid change. In the FI/Ext schedule there are an abundance of responses with short IRTs (see Figure 7 in Sagvolden 2000). Impulsiveness is not present in novel nonthreatening situations initially but develops over time when reinforcers are infrequent (Figure 2, left panel). In the open-field test, the SHR exhibits short runs without stopping or exploring its path (Sagvolden et al 1992a;Wultz and Sagvolden 1992).

[12] 46w Deficient Sustained Attention. In the extinction component of the FI/Ext schedule, SHR resumed responding after a short time, thereby showing deficient sustained attention (see Figure 3 in Sagvolden 2000). Attention is normal when reinforcers are frequent, but poor when reinforcers are infrequent (Figure 2, middle panel).

[13] 48w Hyperactivity. Spontaneously hypertensive rats are hyperactive in the FI/Ext schedule (see Figure 5 in Sagvolden 2000). Hyperactivity, like impulsiveness, is absent in novel situations ( Knardahl and Sagvolden 1979). Spontaneously hypertensive rats are hyperactive when reinforcers are infrequent but not when reinforcers are frequent (Figure 2, right panel).

[14] 48w Other Behavioral Similarities to ADHD. Similar to behavior in children with ADHD, SHR behavior is more variable than WKY (Figure 2), and SHRs have response re-engagement deficits (i.e., inhibiting one response and starting another) when high response rates are induced by the reinforcement schedule (Metzger and Sagvolden 1994).

[15] 67w Conclusion. When SHRs and children with ADHD are tested with the same behavioral schedule, they exhibit all the behavioral characteristics of ADHD as operationalized: sustained attentiondeficit without obvious sensory problems, motor impulsiveness, and hyperactivity that develops over time in novel situations with few reinforcers. Additionally, male SHRs exhibit increased behavioral variability and deficient response re-engagement. Research strongly supports the face validity of the SHR model of ADHD.

[16] 122w Genetics. Three candidate dopaminergic genes (DRD2, DRD4, and DAT-1) were sequenced in SHR and WKY (Mill et al, unpublished data). No differences were found in DRD2 or DRD4 genes, but several variations were found in the DAT-1 gene that are of significance because several ADHD families show linkage to DAT-1. It also strengthens the validity of using WKY as a control for SHR, because their behavioral characteristics are similar to those of other rat strains (Sagvolden 2000). A possible disturbance in the regulation of DAT translation is in agreement with findings that DAT gene expression is transiently reduced in SHR midbrain during the first postnatal month and increased in adult SHR compared with control subjects (Leo et al 2003;Watanabe et al 1997).

[17] 59w Sex Differences. As do ADHD children, SHRs display sex differences. Male SHRs showed more bursts of lever-pressing than females in a FI/Ext schedule of water reinforcement (Berger and Sagvolden 1998). Female SHRs seemed to be less attentive than males because they continued to press the lever after the reinforcer had been delivered (Berger and Sagvolden 1998;Sagvolden and Berger 1996).

[18] 15w Neuropathology. Similar to children with ADHD, SHR have decreased brain volume (Bendel and Eilam 1992).

[19] 81w Neurotransmitter Dysfunction. Dopamine mediates reinforcement processes (Schultz 1998). Thus, dopamine dysfunction might contribute to the altered reinforcement processes of SHR (Sagvolden et al, in press). Although dopamine hypofunction occurs in SHRs (Russell et al 1995(Russell et al , 1998)), it might not be the only factor altering the behavior of this strain (Russell 2003). Two major second messenger systems are impaired in the SHR: cyclic adenosine monophosphate formation (Marcil et al 1997) and calcium influx into neurons (Lehohla et al 2004).

[20] 52w Not only dopamine but also norepinephrine systems seem to be disturbed in SHR (Russell 2003). Norepinephrine, like dopamine, is a modulatory neurotransmitter that strengthens neural circuits that lead to adaptive behavior through interaction with glutamate systems. Dopamine and norepinephrine act in concert to regulate prefrontal cortex function and thereby ensure appropriate behavior.

[21] 45w Delay-of-Reinforcement Gradients. Differences in response rates of SHR and WKY are due to increased reactivity to reinforcers in the SHR (Sagvolden et al 1992b(Sagvolden et al , 1993)). The effects of delayed reinforcers are reduced in SHR, similar to their effects in children with ADHD.

[22] 45w Motor Impulsiveness. Similar to the case in ADHD children, primarily short IRTs are reinforced and maintained by the short delay gradient of SHR (i.e., the relationships between responses with long IRTs are not maintained by reinforcers; Figure 1, right panel; Catania 1971;Catania et al 1988).

[23] 48w Impaired Sustained Attention. The short delay gradient of SHR might prevent the formation of an association between the discriminative stimulus and the reinforcement contingency, resulting in poorer stimulus control and possibly impaired sustained attention during low-reinforcement density (Figure 2) as suggested for ADHD (Sagvolden et al, in press).

[24] 116w Hyperactivity. Hyperactivity in SHR (Figure 2) might be due to a combination of the steeper and shorter delay gradient and deficient extinction (Sagvolden et al, in press). Both factors are probably rooted in a genetically based hypofunctional dopamine system. Similar to its effect in children with ADHD, the effect of a delayed reinforcer is less potent in SHR than in control subjects (Sagvolden 2000). Furthermore, the extinction process also seems to be faulty in SHR. Some investigators have failed to demonstrate hyperactivity in SHR (Ferguson and Cada 2003). This might be because activity was measured for short periods of time and SHRs, like children with ADHD, are hypoactive in a novel environment (Knardahl and Sagvolden 1979).

[25] 45w Behavioral Variability. As in ADHD, increased behavioral variability in SHR (Figure 2) might be caused by the combined effects of a steeper and shorter delay gradient and deficient extinction causing less efficient elimination of ineffective responses (see Figure 7 in Sagvolden et al, in press).

[26] 21w Motor Control Problems. Striatal dopamine hypofunction might be responsible for the motor control problems of SHR (Sagvolden et al, unpublished data).

[27] 66w Psychostimulant Effects. D-amphetamine reduced motor activity and impulsiveness of SHR (Sagvolden, unpublished data). Spontaneously hypertensive rats have reduced behavioral activation in response to methylphenidate and d-amphetamine compared with control WKY (Sagvolden et al 1992b;Wultz et al 1990). The reduced reactivity to these drugs might be associated with abnormalities in DAT-1 gene expression and dopamine hypofunction (Leo et al 2003;Mill et al, unpublished data;Watanabe et al 1997).

[28] 43w A comparison of SHR with WKY revealed decreased stimulusevoked release of dopamine, but greater d-amphetamine-stimulated, transporter-mediated release of dopamine in SHRs, suggesting that SHRs have decreased vesicular stores of dopamine, increased cytoplasmic dopamine, increased DAT, and decreased extracellular dopamine (Russell et al 1998).

[29] 64w The diagnosis of ADHD is behaviorally based; therefore, the validation of an animal model also must be based in behavior. An adequate ADHD model mimics the fundamental behavioral characteristics of ADHD (face validity), conforms to a theoretical rationale for ADHD (construct validity), and predicts aspects of ADHD behavior, genetics, and neurobiology previously clinically unknown (predictive validity). The SHR fulfills many of these validation criteria.

[30] 28w Several other animal models of ADHD have been suggested. These models were developed through genetic manipulation, exposure to toxins, rearing in social isolation, or interference with neurochemical systems.

[31] 77w Wistar-Kyoto Hyperactive Rat. Attempts to breed out hypertension from SHR to determine whether it causes hyperactivity were only partly successful (Sagvolden et al 1992a). This outcome might be because dopamine is a major neuromodulator of both behavior and cortical microcirculation (Krimer et al 1998). Wistar-Kyoto Hyperactive rats (WKHA) are hyperactive but not hypertensive; however, WKHA are not impulsive, and they display hyperreactivity to novel aversive stimuli (Drolet et al 2002;Hendley et al 1986;Sagvolden 2000;Sagvolden et al 1992a).

[32] 112w Naples High-Excitability Rat. Naples high-and low-excitability rats are selectively bred for high and low activity in a Làt maze (Sadile et al 1988). The Naples high-excitability rat (NHE) shows increased reactivity to novel situations and impaired working memory (Gallo et al 2002;Viggiano et al 2002). Naples high-excitability rat behavior has been suggested to result from mesocortical dopamine hyperfunction, because expression of DAT and tyrosine hydroxylase is increased in prefrontal cortex of NHE and dopamine D1 receptors are decreased compared with randomly bred rats. The NHE might be a useful model for ADD because they are inattentive and they do not exhibit hyperactive or impulsive behavior typical of ADHD (Viggiano et al 2002).

[33] 232w Dopamine Transporter Knockout Mouse. Dopamine transporter knockout (DAT-KO) mice lack the gene that codes for DAT-1, which is responsible for synaptic dopamine uptake. These mice are hyperactive in novel situations possibly owing to the fivefold elevation in extracellular dopamine levels within the striatum (Gainetdinov andCaron 2000, 2001;Trinh et al 2003). Dopamine transporter knockout mice are unable to inhibit ongoing behavior and are impaired in learning and memory tasks (Gainetdinov and Caron 2001;Trinh et al 2003). Impulsiveness has not been systematically investigated in the DAT-KO mice. Despite the absence of DAT, psychostimulants are reinforcing to these animals and attenuate their hyperactivity, apparently by mechanisms that involve nondopaminergic systems in limbic areas of the brain (Gainetdinov and Caron 2001;Trinh et al 2003). Whereas inhibitors of the norepinephrine transporter did not affect DAT-KO hyperactivity, drugs that activate the serotonergic system dramatically reduced hyperactivity (Gainetdinov and Caron 2001). The DAT-KO mice provide convincing evidence that hyperactivity induced by high extracellular levels of dopamine can be reduced by enhancing serotonergic tone (i.e., psychostimulants do not act via DAT to reduce hyperactivity in this model; Gainetdinov and Caron 2001). Although this model provides invaluable insight into possible mechanisms of psychostimulant action, the relevance of these findings to ADHD is not immediately obvious because serotonin reuptake inhibitors are of limited use in treating ADHD and one of the side effects is stimulation of motor activity (Gainetdinov and Caron 2001).

[34] 114w Coloboma Mutant Mouse. The Coloboma mutant mouse model is based on the deleted synaptosomal-associated protein 25 (SNAP-25) gene (Barr et al 2000). Deficient SNAP-25 expression causes a triad of phenotypic abnormalities that comprise profound spontaneous hyperactivity, head bobbing, and a prominent eye dysmorphology, as well as delays in neurobehavioral developmental milestones: righting reflex and bar holding (Heyser et al 1995). Heterozygous Coloboma mice (Cm/ϩ) display spontaneous hyperactivity in open field tests that is reduced with d-amphetamine but not methylphenidate (Wilson 2000). The Coloboma mouse is a poor ADHD model because it is predominantly hyperactive, lacks impulsiveness and sustained attention deficit, and has severe neurobiological deficits that would exclude a diagnosis of ADHD in children.

[35] 53w Acallosal Mouse. The acallosal mouse becomes hyperactive over time and shows impaired acquisition in conditioned learning tasks (Magara et al 2000). Impulsiveness, however, measured as latency to enter the arms of a Y-maze, was increased in a novel environment but decreased over time with repeated testing, which is not a characteristic of ADHD.

[36] 65w Hyposexual Rat. A proportion of male rats that fail to copulate with receptive females (less than 50%) are hyperactive and showed a deficit in selective attention. Hyposexual male rats selected for hyperactivity have been suggested as a potential model for ADHD, but their behavior is no different from normally sexual hyperactive rats, and their hyperactivity was not decreased by d-amphetamine (Kohlert 1996;Kohlert and Bloch 1993).

[37] 124w Poor Five-Choice Serial Reaction Time Task Performer. Rats that are selected for poor performance when trained in a five-choice serial reaction time (5-CSRT) task provide a useful model for ADHD in that they are selected for deficient sustained attention, they show poor choice accuracy toward the end of testing sessions, and they demonstrate impulsiveness (Barbelivien et al 2001;Puumala et al 1997). Methylphenidate treatment improved accuracy but did not alter impulsiveness in poor performers (Puumala et al 1997). Interestingly, poor performing rats had low 2-deoxyglucose uptake in cingulate cortex and ventrolateral-orbital cortex, suggesting that the neural network of attention in rats is analogous to that of primates (Barbelivien et al 2001). Poor 5-CSRT task performers are not hyperactive but might provide useful information on ADD.

[38] 37w Wig Rat. Wig (wiggling) rats display hyperactivity and have impaired working memory (Kamimura et al 2001). Wig rats, however, are not an ideal model for ADHD because they display uncharacteristic behavior; they panic when exposed to water.

[1] 26w To be useful, an animal model should provide information that can be used to predict previously unknown aspects of behavior, genetics, and neurobiology of the disorder.

[2] 98w Six-Hydroxydopamine-Lesioned Rat. Neonatal 6-hydroxydopamine-lesioned (6-OHDA-lesioned) rats displayed hyperactivity and impaired learning in a spatial discrimination task, improving after methylphenidate treatment (Davids et al 2003;Shaywitz et al 1978). Hyperactivity was accompanied by decreased striatal DAT, increased DRD4 expression, and altered serotonin function (Kostrzewa et al 1994;Luthman et al 1989;Zhang et al 2001). As in ADHD, neonatal 6-OHDA-lesioned rats showed an initial decrease in spontaneous motor behavior when placed in a novel environment, but after repeated testing, increased activity was observed (Luthman et al 1989). These rats are not impulsive but do provide useful information concerning mechanisms that cause hyperactivity.

[3] 65w Polychlorinated Biphenyl-Exposed Rat. Polychlorinated biphenyls (PCBs) are environmental pollutants with neurotoxic effects that cause developmental abnormalities in human babies, including disruptive behavior and hyperactivity (Berger et al 2001). Male rats administered PCBs, either postnatally or prenatally, demonstrated impulsiveness observed as bursts of activity with short IRTs and hyperactivity, but sustained attention was not impaired (Berger et al 2001;Holene et al 1995Holene et al , 1998)).

[4] 53w Lead-Exposed Mouse. Lead poisoning has been implicated in some cases of human ADHD (Taylor et al 1998). Postnatal exposure in infant mice led to ataxia and hyperactivity that was reduced with d-amphetamine (Silbergeld and Goldberg 1974). Dopaminergic dysfunction and hyperactivity were lead dosedependent and not present in all situations (Kostas et al 1976).

[5] 39w Anoxia in Neonatal Rat. Anoxia increases the risk of ADHD (Lou 1996). Neonatal anoxia caused neurochemical abnormalities in rat monoamine systems as well as transient hyperactivity and spatial memory impairment that persisted into adulthood (Dell'Anna 1999;Dell'Anna et al 1993).

[6] 38w X-Ray Damage of Rat Hippocampus. Exposure to x-ray irradiation damages the hippocampus of rat pups, leading to hyperactivity. These behaviors are ameliorated by d-amphetamine (Highfield et al 1998). This model has not been evaluated for impulsiveness or inattention.

[7] 35w tive attention; the cortical cholinergic projections play a role in stimulus detection, whereas the ascending serotoninergic systems contribute to behavioral inhibition and seem to oppose the functions of other systems in several ways (Robbins 1997).

[8] 48w Nucleus Accumbens Core Lesion. Damage to the nucleus accumbens core causes rats to be hyperactive and to exhibit impulsive choice; however, these rats do not have sustained attention deficit (Cardinal et al 2004). They seemed to exhibit a selective deficit in learning instrumental responses when reinforcers were delayed.

[9] 78w Subthalamic Lesion. Rats with lesions of the subthalamic nucleus showed severely impaired performance in a test of divided and sustained visual attention, including decreased discriminative accuracy, increased and premature anticipatory responding, and perseverative behavior. The accuracy deficit and premature-responding deficit were partially alleviated by increasing the stimulus duration and reducing the waiting period for the stimulus, respectively. Subthalamic nucleus lesions might have multiple, dissociable effects on attention, including discriminative deficits, impulsiveness, and perseverative behavior (Baunez and Robbins 1997).