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.     

The neuropsychopharmacology of attention-deficit/hyperactivity disorder.

More than three decades of research has attempted to elucidate the neuropsychopharmacology of attention-deficit/hyperactivity disorder (ADHD). Stimulants, a principle treatment for the disorder, act on the norepinephrine (NE) and dopamine (DA) systems; this has led to a long-standing hypothesis of catecholamine dysfunction in ADHD. Animal studies show a clear role for NE and DA in the modulation of executive functions, which are often disturbed in persons with ADHD. Nonstimulant agents that are effective in the treatment of ADHD tend to affect the NE system, whereas those affecting only DA, or those that affect neither catecholamine, are less potent in reducing ADHD symptoms. Studies of the effects of NE and DA peripheral metabolites by ADHD pharmacotherapies show acute increases in levels of these catecholamines; however, their long-term turnover may be reduced. Imaging studies suggest stimulants increases DA levels in the brain, whereas some animal models of ADHD are more consistent with excessive DA activation in the disorder. Ultimately, ADHD therapy may modify activity in the NE and DA systems to a more optimal level, thus improving responses to environmental stimuli and enhancing working memory and executive function.     

The nucleus accumbens motor-limbic interface of the spontaneously hypertensive rat as studied in vitro by the superfusion slice technique

The behavioral disturbances of attention-deficit hyperactivity disorder (ADHD) have been attributed to dysfunction of the mesolimbic dopaminergic (DA) projection from the ventral tegmental area of the midbrain. DA released from terminals in the nucleus accumbens (interface between limbic and motor areas of the brain) draws attention to unexpected, behaviorally significant events and provides the motivational drive for reward-related behavior. An in vitro superfusion technique was used to show that depolarization (25 mM K+)-induced release of DA from nucleus accumbens slices of spontaneously hypertensive rats (SHR, animal model for ADHD) was significantly lower than that of Wistar-Kyoto controls (WKY). Evidence also suggested that DA autoreceptor efficacy was increased at low endogenous agonist concentrations. D2 receptor blockade by the antagonist, sulpiride, caused a significantly greater increase in the electrically stimulated release of DA from nucleus accumbens slices of SHR compared to WKY. This suggested that presynaptic regulation of DA release had been altered in SHR to cause down-regulation of the DA system. This could have occurred at an early stage of development in an attempt to compensate for abnormally high DA concentrations. The reduction in DA transmission could have left the adult SHR with impaired DA reward/reinforcement mechanisms, resulting in the behavioral disturbances characteristic of ADHD.     

Serotoninergics attenuate hyperlocomotor activity in rats. Potential new therapeutic strategy for hyperactivity

Hyperactivity is thought to be associated with an alteration of dopamine (DA) neurochemistry in brain. This conventional view became solidified on the basis of observed hyperactivity in DA-lesioned animals and effectiveness of the dopaminomimetics such amphetamine (AMP) in abating hyperactivity in humans and in animal models of hyperactivity. However, because AMP releases serotonin (5-HT) as well as DA, we investigated the potential role of 5-HT in an animal model of hyperactivity. We found that a greater intensity of hyperactivity was produced in rats when both DA and 5-HT neurons were damaged at appropriate times in ontogeny. Therefore, previously we proposed this as an animal model of attention deficit hyperactivity disorder (ADHD) - induced by destruction of dopaminergic neurons with 6-hydroxydopamine (6-OHDA) (neonatally) and serotoninergic neurons with 5,7-dihydroxytryptamine (5,7-DHT) (in adulthood). In this model effects similar to that of AMP (attenuation of hyperlocomotion) were produced by m-chlorophenylpiperazine (m-CPP) but not by 1-phenylbiguanide (1-PG), respective 5-HT2 and 5-HT3 agonists. The effect of m-CPP was shown to be replicated by desipramine, and was largely attenuated by the 5-HT2 antagonist mianserin. These findings implicate 5-HT neurochemistry as potentially important therapeutic targets for treating human hyperactivity and possibly childhood ADHD.     

Molecular biology, pharmacology and functional role of the plasma membrane dopamine transporter

The plasma membrane dopamine transporter (DAT) tightly regulates the extracellular concentrations of dopamine (DA) by re-capturing released neurotransmitter back into the presynaptic neuronal terminals and/or neighboring DA projections thereby providing an effective way to regulate synaptic and extrasynaptic DA levels. This transporter is a primary target of many potent psychotropic drugs and neurotoxins, such as cocaine, amphetamines and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this review we summarize recent advances in understanding the structure, regulation, and functional roles of DAT in normal DA physiology and pathological conditions, such as attention deficit hyperactivity disorder (ADHD) and neurodegenerative processes, as well as their contribution to the pharmacology of psychostimulant drugs. Significant new insights on these issues have been gained using mice with genetic deletion of DAT.     

Neurobiology of animal models of attention-deficit hyperactivity disorder

Attention-deficit hyperactivity disorder (ADHD) is a heterogeneous, highly heritable, disorder resulting from complex gene-gene and gene-environment interactions. The defining symptoms of hyperactivity, impulsivity and impaired sustained attention are not unique to ADHD. It is therefore not surprising that animals with distinctly different neural defects model the behavioural characteristics of the disorder. Consistent with ADHD being a developmental disorder, animal models are either genetic (spontaneously hypertensive rats (SHR), dopamine transporter (DAT) knock-out mice, SNAP-25 mutant mice, mice expressing a mutant thyroid receptor) or have suffered an insult to the central nervous system during the early stages of development (anoxia, 6-hydroxydopamine). It appears that neural transmission is impaired by either direct disruption of dopaminergic transmission or a more general impairment of neurotransmission that gives rise to compensatory changes in monoaminergic systems that are not sufficient to completely normalize neural function. In general, results obtained with animal studies suggest that dopamine neurons are functionally impaired. However, evidence obtained from some animal models suggests that the noradrenergic and serotonergic neurotransmitter systems may be the target of drugs that ameliorate ADHD symptoms.     

Reprint of "Neurobiology of animal models of attention-deficit hyperactivity disorder"

Attention-deficit hyperactivity disorder (ADHD) is a heterogeneous, highly heritable, disorder resulting from complex gene-gene and gene-environment interactions. The defining symptoms of hyperactivity, impulsivity and impaired sustained attention are not unique to ADHD. It is therefore not surprising that animals with distinctly different neural defects model the behavioural characteristics of the disorder. Consistent with ADHD being a developmental disorder, animal models are either genetic (spontaneously hypertensive rats (SHR), dopamine transporter (DAT) knock-out mice, SNAP-25 mutant mice, mice expressing a mutant thyroid receptor) or have suffered an insult to the central nervous system during the early stages of development (anoxia, 6-hydroxydopamine). It appears that neural transmission is impaired by either direct disruption of dopaminergic transmission or a more general impairment of neurotransmission that gives rise to compensatory changes in monoaminergic systems that are not sufficient to completely normalize neural function. In general, results obtained with animal studies suggest that dopamine neurons are functionally impaired. However, evidence obtained from some animal models suggests that the noradrenergic and serotonergic neurotransmitter systems may be the target of drugs that ameliorate ADHD symptoms.     

Structure and function of dopamine receptors

Dopamine (DA) is the most abundant catecholamine in the brain. The involvement and importance of DA as a neurotransmitter in the regulation of different physiological functions in the central nervous system (CNS) is well known. Deregulation of the dopaminergic system has been linked with Parkinson's disease, Tourette's syndrome, schizophrenia, attention deficit hyperactive disorder (ADHD) and generation of pituitary tumours. This review focuses on the pharmacological and biochemical features shared by the dopamine receptors. We address their coupling to secondary messenger pathways and their physiological function based upon studies using pharmacological tools, specific brain lesions and, more recently, genetically modified animal models.     

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 α₂-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.     

Altered dopaminergic function in the prefrontal cortex, nucleus accumbens and caudate-putamen of an animal model of attention-deficit hyperactivity disorder — the spontaneously hypertensive rat

The spontaneously hypertensive rat (SHR) has been proposed as an animal model for Attention-Deficit Hyperactivity Disorder (ADHD). The behavioural problems of ADHD have been suggested to be secondary to altered reinforcement mechanisms resulting from dysfunction of the mesolimbic and mesocortical dopaminergic systems. The present study therefore investigated whether there are regional differences in dopamine (DA) and acetylcholine (ACh) release and DA D₂-receptor function in SHR compared to their normotensive Wistar-Kyoto (WKY) controls. The DA D₂-receptor agonist, quinpirole, caused significantly greater inhibition of DA release from caudate-putamen but not from nucleus accumbens or prefrontal cortex slices of SHR relative to WKY. DA D₂-receptor blockade by the antagonist, sulpiride, caused a significantly greater increase in DA release from nucleus accumbens slices of SHR compared to WKY suggesting increased efficacy of DA autoreceptors at low endogenous agonist concentrations in the nucleus accumbens of SHR. The electrically-stimulated release of DA was significantly lower in caudate-putamen and prefrontal cortex slices of SHR than in slices of WKY. This could be attributed to increased autoreceptor-mediated inhibition of DA release in caudate-putamen slices but not in the prefrontal cortex. No difference was observed between SHR and WKY with respect to DA D₂-receptor-mediated inhibition of ACh release from caudate-putamen or nucleus accumbens slices, suggesting that postsynaptic DA D₂-receptor function is not altered in SHR relative to WKY.     

Schizophrenia: do all roads lead to dopamine or is this where they start? Evidence from two epidemiologically informed developmental rodent models

The idea that there is some sort of abnormality in dopamine (DA) signalling is one of the more enduring hypotheses in schizophrenia research. Opinion leaders have published recent perspectives on the aetiology of this disorder with provocative titles such as ‘Risk factors for schizophrenia—all roads lead to dopamine'' or ‘The dopamine hypothesis of schizophrenia—the final common pathway''. Perhaps, the other most enduring idea about schizophrenia is that it is a neurodevelopmental disorder. Those of us that model schizophrenia developmental risk-factor epidemiology in animals in an attempt to understand how this may translate to abnormal brain function have consistently shown that as adults these animals display behavioural, cognitive and pharmacological abnormalities consistent with aberrant DA signalling. The burning question remains how can in utero exposure to specific (environmental) insults induce persistent abnormalities in DA signalling in the adult? In this review, we summarize convergent evidence from two well-described developmental animal models, namely maternal immune activation and developmental vitamin D deficiency that begin to address this question. The adult offspring resulting from these two models consistently reveal locomotor abnormalities in response to DA-releasing or -blocking drugs. Additionally, as adults these animals have DA-related attentional and/or sensorimotor gating deficits. These findings are consistent with many other developmental animal models. However, the authors of this perspective have recently refocused their attention on very early aspects of DA ontogeny and describe reductions in genes that induce or specify dopaminergic phenotype in the embryonic brain and early changes in DA turnover suggesting that the origins of these behavioural abnormalities in adults may be traced to early alterations in DA ontogeny. Whether the convergent findings from these two models can be extended to other developmental animal models for this disease is at present unknown as such early brain alterations are rarely examined. Although it is premature to conclude that such mechanisms could be operating in other developmental animal models for schizophrenia, our convergent data have led us to propose that rather than all roads leading to DA, perhaps, this may be where they start.     

Current animal models of obsessive compulsive disorder: a critical review

During the last 30 years there have been many attempts to develop animal models of obsessive compulsive disorder (OCD), in the hope that they may provide a route for furthering our understanding and treatment of this disorder. The present paper reviews current genetic, pharmacological and behavioral animal models of OCD, and evaluates their face validity (derived from phenomenological similarity between the behavior in the animal model and the specific symptoms of the human condition), predictive validity (derived from similarity in response to treatment) and construct validity (derived from similarity in the underlying mechanisms--physiological or psychological).     

Rodent models: utility for candidate gene studies in human attention-deficit hyperactivity disorder (ADHD)

Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioral disorder defined by symptoms of developmentally inappropriate inattention, impulsivity and hyperactivity. Behavioral genetic studies provide overwhelming evidence for a significant genetic role in the pathogenesis of the disorder. Rodent models have proven extremely useful in helping understand more about the genetic basis of ADHD in humans. A number of well-characterized rodent models have been proposed, consisting of inbred strains, selected lines, genetic knockouts, and transgenic animals, which have been used to inform candidate gene studies in ADHD. In addition to providing information about the dysregulation of known candidate genes, rodents are excellent tools for the identification of novel ADHD candidate genes. While not yet widely used to identify genes for ADHD-like behaviors in rodents, quantitative trait loci (QTL) mapping approaches using recombinant inbred strains, heterogeneous stock mice, and chemically mutated animals have the potential to revolutionize our understanding of the genetic basis of ADHD.     

Effects of neonatal dietary manganese exposure on brain dopamine levels and neurocognitive functions

Neonatal exposure to high levels of manganese (Mn) has been indirectly implicated as a causal agent in attention deficit hyperactivity disorder (ADHD), since Mn toxicity and ADHD both involve dysfunction in brain dopamine (DA) systems. This study was undertaken to examine this putative relationship in an animal model by determining if levels of neonatal dietary Mn exposure were related to brain DA levels and/or behavioral tests of executive function (EF) when the animals reached maturity. We used 32 newborn male Sprague-Dawley rats and randomly assigned them to one of the four dietary Mn supplementation conditions: 0, 50, 250 and 500 microg per day, administered daily in water from postnatal days 1-21. During days 50-64, the animals were given a burrowing detour test and a passive avoidance test. At day 65, the animals were killed and brains were assayed for DA. There was a statistically significant relationship (P = 0.003) between dietary Mn exposure and striatal DA. On the burrowing detour and passive avoidance, greater deficits were observed for animals subjected to higher Mn exposure, but these differences did not reach statistical significance. However, tests for heterogeneity of variance between groups were statistically significant for all measures, with positive relationship between Mn exposure and degree of within-group behavioral variability. Kendall's nonparametric test of the relationship between the three behavioral measures and striatal DA levels was also statistically significant (P = 0.02). These results lend support to the hypothesis that neonatal Mn exposure is related to brain DA levels and neurocognitive deficit in the rodent.     

Adults with attention-deficit/hyperactivity disorder: current concepts

In recent years, the validity of attention-deficit/hyperactivity disorder (ADHD) in adulthood has gained acceptance among mental health researchers and clinicians. This article will outline the history of this process, provide our best understanding of the characteristics of ADHD in adulthood, review current guidelines and controversies in the assessment of adult ADHD, and summarize pharmacological and psychosocial treatment options. Despite the strides gained in understanding adult ADHD, the authors encourage more research on this population and caution that current conceptualizations of the disorder are based on a limited amount of empirically based knowledge.     

Genetic findings in Attention-Deficit and Hyperactivity Disorder (ADHD)

Attention-Deficit and Hyperactivity Disorder (ADHD) is a common child and adolescent psychiatric disorder with a prevalence rate of 3-7%. Formal genetic studies provided an estimated heritability of 0.6-0.8 and an approximately five-fold elevated risk for ADHD in first-degree relatives. Currently, four genome scans have led to the identification of chromosomal regions potentially relevant in ADHD; especially the evidence for linkage to chromosome 5p13 is convincing. Meta-analyses of a large number of candidate gene studies suggest association with gene variants of the dopaminergic receptors DRD4 and DRD5, the serotonergic receptor HTR1B, and the synaptosomal receptor protein (SNAP-25). Hyperactivity has been investigated particularly in animal models, focusing on knockout- and quantitative trait loci (QTL) designs, with promising results for the dopaminergic system. It is likely that several gene polymorphisms with moderate to small effect sizes contribute to the phenotype ADHD; different combinations of such predisposing variants presumably underlie ADHD in different individuals. Therefore, large samples for molecular genetic studies are mandatory to detect these polymorphisms. Accordingly, several of today's findings have to be regarded as preliminary. The understanding of ADHD's neurobiology may be advanced by new technologies, such as SNP-based genome scans performed with gene chips comprising 10,000-1,000,000 SNPs, as well as using more sophisticated animal model designs.     

Functional consequences of attention‐deficit hyperactivity disorder on children and their families

Attention‐deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with core symptoms that include hyperactivity, impulsiveness, and inattention, and it is the most common psychiatric disorder among children and adolescents. These core symptoms are continuously recognized throughout the day from childhood to adulthood. Furthermore, children with ADHD from childhood to adulthood might also have various comorbid psychiatric disorders. Recently, bipolar disorder and disruptive mood dysregulation disorder, a new clinical issue, have been discussed as comorbid disorders or differential disorders associated with ADHD. Furthermore, comorbid disorders of ADHD are related to quality of life and family burden. Children with ADHD have poorer long‐term outcomes than controls with respect to: academic achievement and attainment, occupational rank and job performance, risky sexual practices and early unwanted pregnancies, substance use, relationship difficulties, marital problems, traffic violations, and car accidents. Irritability of children with ADHD has been a key symptom that clinicians and researchers have used to evaluate the developmental condition of children with ADHD. ADHD is sometimes a chronic disorder that occurs over a long period, increasing the family burden of these children (including health‐care costs), which will increase with aging for unremitted children with ADHD. Therefore, clinicians should evaluate not only the mental condition of the child but also the family burden. Children with ADHD should be treated during childhood to reduce their clinical symptoms and family burden.     

Pharmacological models of ADHD

Summary For more than 50 years, heavy metal exposure during pre- or post-natal ontogeny has been known to produce long-lived hyperactivity in rodents. Global brain injury produced by neonatal hypoxia also produced hyperactivity, as did (mainly) hippocampal injury produced by ontogenetic exposure to X-rays, and (mainly) cerebellar injury produced by the ontogenetic treatments with the antimitotic agent methylazoxymethanol or with polychlorinated biphenyls (PCBs). More recently, ontogenetic exposure to nicotine has been implicated in childhood hyperactivity. Because attention deficits most often accompany the hyperactivity, all of the above treatments have been used as models of attention deficit hyperactivity disorder (ADHD). However, the causation of childhood hyperactivity remains unknown. Neonatal 6-OHDA-induced dopaminergic denervation of rodent forebrain also produces hyperactivity – and this model, or variations of it, remain the most widely-used animal model of ADHD. In all models, amphetamine (AMPH) and methylphenidate (MPH), standard treatments of childhood ADHD, typically attenuate the hyperactivity and/or attention deficit. On the basis of genetic models and the noted animal models, monoaminergic phenotypes appear to most-closely attend the behavioral dysfunctions, notably dopaminergic, noradrenergic and serotoninergic systems in forebrain (basal ganglia, nucleus accumbens, prefrontal cortex). This paper describes the various pharmacological models of ADHD and attempts to ascribe a neuronal phenotype with specific brain regions that may be associated with ADHD. Correspondence: Richard M. Kostrzewa, Department of Pharmacology, Quillen College of Medicine, East Tennessee State University, Johnson City, Box 70577, TN 37614, USA     

A prenatal nicotine exposure mouse model of methylphenidate responsive ADHD-associated cognitive phenotypes

Prenatal exposure to nicotine via cigarette smoke or other forms of tobacco use is a significant environmental risk factor for attention deficit hyperactivity disorder (ADHD). The neurobiological mechanisms underlying the link between prenatal nicotine exposure (PNE) and ADHD are not well understood. Animal models, especially rodent models, are beginning to bridge this gap in knowledge. Although ADHD is characterized by hyperactivity, inattention, impulsivity and working memory deficits, the majority of the animal models are based on only one or two ADHD associated phenotypes, in particular, hyperactivity or inattention. We report a PNE mouse model that displays the full range of ADHD associated behavioral phenotypes including working memory deficit, attention deficit and impulsive-like behavior. All of the ADHD-associated phenotypes respond to a single administration of a therapeutic equivalent dose of methylphenidate. In an earlier study, we showed that PNE produces hyperactivity, frontal cortical hypodopaminergic state and thinning of the cingulate cortex. Collectively, these data suggest that the PNE mouse model recapitulates key features of ADHD and may be a suitable preclinical model for ADHD research.     

Imaging the effects of methylphenidate on brain dopamine: new model on its therapeutic actions for attention-deficit/hyperactivity disorder.

Methylphenidate hydrochloride (MP) is an effective treatment for attention-deficit/hyperactivity disorder (ADHD), a common neurobehavioral disorder of childhood onset characterized by inattention, hyperactivity, and distractibility. Methylphenidate hydrochloride blocks the dopamine transporters (DAT), the main mechanism for removing dopamine (DA) from the synapse, is believed to be involved in its therapeutic properties. However, the mechanism(s) by which increases in DA improve symptomatology in ADHD are not completely understood. Our studies of the dopaminergic effects of MP in the human brain using positron emission tomography (PET) have shown that MP blocks DAT, and that extracellular DA increases in proportion to the level of blockade and the rate of DA release (modulated by DA cell firing). These DA increases are greater when MP is given concomitantly with a salient stimulus than with a neutral stimulus, documenting the context dependency of MP effects. Additionally, MP-induced increases in DA are associated with an enhanced perception of the stimulus as salient. We postulate the MP's therapeutic effects are due in part to its ability to enhance the magnitude of DA increases induced by stimuli that by themselves generate weak responses, enhancing their saliency and the attention and interest they elicit. We postulate that these effects would improve school performance.