Increased noradrenergic activity in prefrontal cortex slices of an animal model for attention-deficit hyperactivity disorder--the spontaneously hypertensive rat

Spontaneously hypertensive rats (SHR) are used as a model for attention-deficit/hyperactivity disorder (ADHD) since SHR are hyperactive and they show defective sustained attention in behavioral tasks. Using an in vitro superfusion technique we showed that norepinephrine (NE) release from prefrontal cortex slices of SHR was not different from that of their Wistar-Kyoto (WKY) control rats when stimulated either electrically or by exposure to buffer containing 25 mM K(+). The monoamine vesicle transporter is, therefore, unlikely to be responsible for the deficiency in DA observed in SHR, since, in contrast to DA, vesicle stores of NE do not appear to be depleted in SHR. In addition, alpha(2)-adrenoceptor mediated inhibition of NE release was reduced in SHR, suggesting that autoreceptor function was deficient in prefrontal cortex of SHR. So, while DA neurotransmission appears to be down-regulated in SHR, the NE system appears to be under less inhibitory control than in WKY suggesting hypodopaminergic and hypernoradrenergic activity in prefrontal cortex of SHR. These findings are consistent with the hypothesis that the behavioral disturbances of ADHD are the result of an imbalance between NE and DA systems in the prefrontal cortex, with inhibitory DA activity being decreased and NE activity increased relative to controls.     

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.     

Spontaneously hypertensive rat (SHR) as an animal model for ADHD: a short overview

Diverse studies indicate that attention-deficit hyperactivity disorder (ADHD) is associated with alterations in encoding processes, including working or short-term memory. Some ADHD dysfunctional domains are reflected in the spontaneously hypertensive rat (SHR). Because ADHD, drugs and animal models are eliciting a growing interest, hence the aim of this work is to present a brief overview with a focus on the SHR as an animal model for ADHD and memory deficits. Thus, this paper reviews the concept of SHR as a model system for ADHD, comparing SHR, Wistar-Kyoto and Sprague-Dawley rats with a focus on the hypertension level and working, short-term memory and attention in different behavioral tasks, such as open field, five choice serial reaction time, water maze, passive avoidance, and autoshaping. In addition, drug treatments (d-amphetamine and methylphenidate) are evaluated.     

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.     

Sequence analysis of <Emphasis Type="Italic">Drd2</Emphasis>, <Emphasis Type="Italic">Drd4</Emphasis>, and <Emphasis Type="Italic">Dat1</Emphasis> in SHR and WKY rat strains

Background  

The Spontaneously Hypertensive Rat (SHR) shows a number of behaviours that closely parallel those seen in children with attention-deficit hyperactivity disorder. These include motor hyperactivity, excessive responses under a fixed-interval/extinction schedule, difficulty in acquiring operant tasks and increased sensitivity to immediate behavioural reinforcement. As in children with ADHD, the behavioural and cognitive deficits in the SHR are responsive to stimulants, including d-amphetamine and d,l-methylphenidate. The non-hyperactive Wistar Kyoto (WKY) rat strain is often used as a control in behavioural studies of the SHR, and WKY itself has been suggested to be a useful animal model of depression. Numerous studies have shown that dopaminergic neurotransmission is altered between the two strains. Human genetic studies have found associations between several dopaminergic genes and both ADHD and depression.     

Impact of emotional salience on episodic memory in attention-deficit/hyperactivity disorder: a functional magnetic resonance imaging study.

BACKGROUND: Patients with attention-deficit/hyperactivity disorder (ADHD) show episodic memory deficits especially in complex memory tasks. We investigated the neural correlates of memory formation in ADHD and their modulation by stimulus salience. METHODS: We recorded event-related functional magnetic resonance imaging during an episodic memory paradigm with neutral and emotional pictures in 12 male ADHD subjects and 12 healthy adolescents. RESULTS: Emotional salience did significantly augment memory performance in ADHD patients. Successful encoding of neutral pictures was associated with activation of the anterior cingulate cortex (ACC) in healthy adolescents but with activation of the superior parietal lobe (SPL) and precuneus in ADHD patients. Successful encoding of emotional pictures was associated with prefrontal and inferior temporal cortex activation in both groups. Healthy adolescents, moreover, showed deactivation in the inferior parietal lobe. CONCLUSIONS: From a pathophysiological point of view, the most striking functional differences between healthy adolescents and ADHD patients were in the ACC and SPL. We suggest that increased SPL activation in ADHD reflected attentional compensation for low ACC activation during the encoding of neutral pictures. The higher salience of emotional stimuli, in contrast, regulated the interplay between ACC and SPL in conjunction with improving memory to the level of healthy adolescents.     

Conditional cross-correlation analysis of thalamocortical neurotransmission

Evidence supports dysfunction of dopaminergic and noradrenergic systems in patients with attention-deficit hyperactivity disorder (ADHD). Noradrenergic and dopaminergic systems exert distinct modulatory actions on the transfer of information through neural circuits that connect functionally distinct cortical areas with separate striatal regions and remain segregated in parallel striato–pallidal–thalamic and striato–substantia nigra pars reticulata–thalamic pathways. Prefrontal cortex performance is maximal at moderate stimulation of postsynaptic dopaminergic and noradrenergic receptors, and is reduced by either higher or lower levels of receptor stimulation. Spontaneously hypertensive rats (SHR) are generally considered to be a suitable genetic model for ADHD, since they display hyperactivity, impulsivity, poor stability of performance, impaired ability to withhold responses and poorly sustained attention, when compared with their normotensive Wistar–Kyoto (WKY) control rats. Evidence suggests that terminals of mesocortical, mesolimbic and nigrostriatal dopaminergic neurons of SHR release less dopamine in response to electrical stimulation and/or depolarization as a result of exposure to high extracellular K⁺ concentrations, than WKY. Vesicular storage of dopamine was suggested to be impaired in SHR, causing leakage of dopamine into the cytoplasm and increased d-amphetamine-induced transporter-mediated release. While electrically stimulated release of dopamine appears to be decreased in prefrontal cortex of SHR suggesting hypodopaminergic function, autoreceptor-mediated inhibition of norepinephrine release appears to be impaired in SHR, suggesting that noradrenergic function may be poorly regulated in the prefrontal cortex of the SHR. These findings are consistent with the hypothesis that the behavioral disturbances of ADHD are the result of an imbalance between noradrenergic and dopaminergic systems in the prefrontal cortex, with inhibitory dopaminergic activity being decreased and noradrenergic activity increased relative to controls.     

Behavioral and cognitive subtypes of ADHD

Attention-deficit hyperactivity symptoms are observed by teachers in 9.2% of a nonreferred elementary school population. Two subtypes of attention-deficit hyperactivity disorder (ADHD), a cognitive form and a behavioral form, are identified. The behavioral subtype includes about 80% of those identified and is characterized by distinct clinical phenomenology of inattention, impulsivity, and hyperactivity. These children can be described on a continuum of severity, with the most severe showing behavioral features indistinguishable from conduct disorder. Children with behavioral subtypes of ADHD do not exhibit the specific skill deficits on neuropsychological tests that are characteristic of reading disabled children. There is a second, less prevalent type of cognitive attention-deficit hyperactivity disorder constituting approximately 20% of ADHD children that includes severe academic underachievement along with inattention, impulsivity, and overactivity. Children with the cognitive subtype exhibit information processing deficits that involve inadequate encoding and retrieval of linguistic information, characteristic of reading disabilities.     

Effect of amphetamine, cocaine and depolarization by high potassium on extracellular dopamine in the nucleus accumbens shell of SHR rats. An in vivo microdyalisis study

Spontaneously hypertensive rats (SHR) exhibit behavioural abnormalities (hyperactivity and hyper reactivity to stress) that resemble the behavioural abnormalities of human attention-deficit with hyperactivity disorder (ADHD). Because dopamine has been implicated in ADHD we studied by in vivo microdialysis the dopamine output in the nucleus accumbens (NAc) shell of 6 week-old (pre-hypertensive stage) SHR rats and in their normotensive age matched Wistar Kyoto controls (WKY). We observed that SHR rats had significant higher basal dialysate dopamine concentrations (about 20%) than WKY. Systemic administration of amphetamine (0.25 and 0.5 mg/kg s.c.), and methylphenidate (1 and 2 mg/kg i.p.) produced an higher increase in dialysate dopamine in the NAc shell of SHR rats as compared with WKY rats, although only after the administration of the lowest dose of amphetamine and methylphenidate this difference was found to be significant. In contrast when the microdialysis fiber was perfused by 30 or 60 mM K(+), a lower increase of dialysate dopamine was observed in SHR rats as compared with WKY rats. These apparently contradictory results can be explained by postulating that SHR rats have a higher tone of NAc shell dopamine transmission and synthesis associated with a lower storage capacity of vesicles in dopamine terminals of the same area.     

Methylphenidate affects striatal dopamine differently in an animal model for attention-deficit/hyperactivity disorder--the spontaneously hypertensive rat

The spontaneously hypertensive rat (SHR) is used as a model for attention-deficit/hyperactivity disorder (ADHD) because it has behavioural characteristics (hyperactivity, impulsiveness, poorly sustained attention) similar to those of ADHD. ADHD children have been shown to have reduced striatal activation in certain tasks. SHR have reduced striatal dopamine release in response to electrical stimulation. The present study set out to investigate possible long-term effects of methylphenidate treatment on dopaminergic function in striatal slices of SHR compared to their normotensive Wistar-Kyoto (WKY) control rats. Methylphenidate treatment (3 mg/kg daily for 14 days) did not normalize the decreased electrically-stimulated release of [(3)H]dopamine from SHR caudate-putamen slices nor did it affect postsynaptic D(2) receptor function. However, the second electrical stimulus caused a relatively greater release of [(3)H]dopamine from caudate-putamen slices of methylphenidate-treated SHR than from vehicle-treated SHR, suggesting that presynaptic mechanisms controlling dopamine release had been altered. Interestingly, [(3)H]dopamine release from WKY caudate-putamen slices in response to D(2) autoreceptor blockade by the antagonist, sulpiride, was selectively increased by methylphenidate treatment. This effect was not seen in SHR possibly because D(2) autoreceptor function had already been up-regulated. The results show that methylphenidate is unable to enhance D(2) autoreceptor function in SHR.     

Familial vulnerability to ADHD affects activity in the cerebellum in addition to the prefrontal systems

OBJECTIVE: Familial vulnerability to attention-deficit/hyperactivity disorder (ADHD) has been shown to be related to atypical prefrontal activity during cognitive control tasks. However, ADHD is associated with deficits in the cerebellum as well as deficits in frontostriatal circuitry and associated cognitive control. In this study, we investigated whether cerebellar systems are sensitive to familial risk for ADHD in addition to frontostriatal circuitry. METHOD: We used an event-related, rapid mixed-trial functional magnetic resonance imaging design. The paradigm was a variation on a go/no-go task, with expected (go) and unexpected (no-go) events at expected and unexpected times. A total of 36 male children and adolescents completed the study, including 12 sibling pairs discordant for ADHD and 12 matched controls. RESULTS: Children and adolescents with ADHD were less accurate on unexpected events than control subjects. Performance by unaffected siblings was intermediate, between that of children and adolescents with ADHD and controls. Functional neuroimaging results showed dissociation between activation in the cerebellum and anterior cingulate cortex: Activity in the anterior cingulate cortex was decreased for subjects with ADHD and their unaffected siblings compared with controls for manipulations of stimulus type (no-go trials), but not timing. In contrast, cerebellar activity was decreased for subjects with ADHD and their unaffected siblings for manipulations of timing, but not stimulus type. CONCLUSIONS: These findings suggest that activity in both the prefrontal cortex and cerebellum is sensitive to familial vulnerability to ADHD. Unaffected siblings of individuals with ADHD show deficits similar to affected probands in prefrontal areas for unexpected events and in cerebellum for events atunexpected times.     

Dopamine hypofunction possibly results from a defect in glutamate-stimulated release of dopamine in the nucleus accumbens shell of a rat model for attention deficit hyperactivity disorder--the spontaneously hypertensive rat

RUSSELL, V.A. Dopamine hypofunction possibly results from a defect in glutamate-stimulated release of dopamine in the nucleus accumbens shell of a rat model for attention deficit hyperactivity disorder-the spontaneously hypertensive rat. NEUROSCI. BIOBEHAV. REV.27(2003). Disturbances in glutamate, dopamine and norepinephrine function in the brain of a genetic animal model for attention-deficit hyperactivity disorder (ADHD), the spontaneously hypertensive rat (SHR), and information obtained from patients with ADHD, suggest a defect in neuronal circuits that are required for reward-guided associative learning and memory formation. Evidence derived from (i). the neuropharmacology of drugs that are effective in treating ADHD symptoms, (ii). molecular genetic and neuroimaging studies of ADHD patients, as well as (iii). the behaviour and biochemistry of animal models, suggests dysfunction of dopamine neurons. SHR have decreased stimulation-evoked release of dopamine as well as disturbances in the regulation of norepinephrine release and impaired second messenger systems, cAMP and calcium. In addition, evidence supports a selective deficit in the nucleus accumbens shell of SHR which could contribute to impaired reinforcement of appropriate behaviour.     

Norepinephrine and dopamine modulate impulsivity on the five-choice serial reaction time task through opponent actions in the shell and core sub-regions of the nucleus accumbens

Impulsive behavior is a hallmark of several neuropsychiatric disorders (eg, attention-deficit/hyperactivity disorder, ADHD). Although dopamine (DA) and norepinephrine (NE) have a significant role in the modulation of impulsivity their neural loci of action is not well understood. Here, we investigated the effects of the selective NE re-uptake inhibitor atomoxetine (ATO) and the mixed DA/NE re-uptake inhibitor methylphenidate (MPH), both with proven clinical efficacy in ADHD, on the number of premature responses on a five-choice serial reaction time task, an operational measure of impulsivity. Microinfusions of ATO into the shell, but not the core, sub-region of the nucleus accumbens (NAcb) significantly decreased premature responding whereas infusions of MPH in the core, but not the shell, sub-region significantly increased premature responding. However, neither ATO nor MPH significantly altered impulsive behavior when infused into the prelimbic or infralimbic cortices. The opposing effects of ATO and MPH in the NAcb core and shell on impulsivity were unlikely mediated by ancillary effects on behavioral activation as locomotor activity was either unaffected, as in the case of ATO infusions in the core and shell, or increased when MPH was infused into either the core and shell sub-region. These findings indicate an apparently 'opponent' modulation of premature responses by NE and DA in the NAcb shell or core, respectively, and suggest that the symptom clusters of hyperactive-impulsive type ADHD may have distinct neural and neurochemical substrates.     

Differences in executive functioning in children with heavy prenatal alcohol exposure or attention-deficit/hyperactivity disorder.

Children with either fetal alcohol spectrum disorder (FASD) or attention-deficit/hyperactivity disorder (ADHD) display deficits in attention and executive function (EF) and differential diagnosis of these two clinical groups may be difficult, especially when information about prenatal alcohol exposure is unavailable. The current study compared EF performance of three groups: children with heavy prenatal alcohol exposure (ALC); nonexposed children with attention-deficit/hyperactivity disorder (ADHD); and typically developing controls (CON). Both clinical groups met diagnostic criteria for ADHD. The EF tasks used were the Wisconsin Card Sorting Test (WCST), the Controlled Oral Word Association Test (COWAT), and the Trail Making Test (TMT). Results indicated different patterns of deficit; both clinical groups displayed deficits on the WCST and a relative weakness on letter versus category fluency. Only the ALC group displayed overall deficits on letter fluency and a relative weakness on TMT-B versus TMT-A. In addition, WCST performance was significantly lower than expected based on IQ in the ADHD group and significantly higher than expected in the ALC group. These results, which indicate that, although EF deficits occurred in both clinical groups, the degree and pattern of deficit differed between the ALC and ADHD groups, may improve differential diagnosis.     

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.     

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 neural correlates of deficient error awareness in attention-deficit hyperactivity disorder (ADHD)

The ability to detect and correct errors is critical to adaptive control of behaviour and represents a discrete neuropsychological function. A number of studies have highlighted that attention-deficit hyperactivity disorder (ADHD) is associated with abnormalities in behavioural and neural responsiveness to performance errors. One limitation of previous work has been a failure to determine the extent to which these differences are attributable to failures of conscious error awareness, a process that is dependent on the integrity of the frontal lobes. Recent advances in electrophysiological research make it possible to distinguish unconscious and conscious aspects of error processing. This study constitutes an extensive electrophysiological investigation of error awareness and error processing in ADHD. A Go/No-Go response inhibition task specifically designed to assess error awareness was administered to a group of adults diagnosed with ADHD and a group of matched control participants. The ADHD group made significantly more errors than the control group but was less likely to consciously detect these errors. An analysis of event-related potentials elicited by errors indicated that an early performance monitoring component (early positivity) was significantly attenuated in the ADHD group as was a later component that specifically reflects conscious error processing (Pe). Dipole source modelling suggested that abnormal Pe amplitudes were attributable to decreased activation of the anterior cingulate cortex. Decreased electrodermal activity in the ADHD group also suggested a motivational insensitivity to performance errors. Our data provide evidence that neuropsychological deficits associated with ADHD can be exacerbated by error processing abnormalities. Error awareness may represent an important cognitive and physiological phenotype for ADHD.     

Increased Prefrontal Oxygenation Related to Distractor-Resistant Working Memory in Children with Attention-Deficit/Hyperactivity Disorder (ADHD)

This study aimed at investigating the effect of distraction on working memory and its underlying neural mechanisms in children with attention-deficit/hyperactivity disorder (ADHD). To this end, we studied hemodynamic activity in the prefrontal cortex using near-infrared spectroscopy while 16 children with ADHD and 10 typically developing (TD) children performed a working memory task. This task had two conditions: one involved a distraction during the memory delay interval, whereas the other had no systematic distraction. The ADHD patients showed significantly poorer behavioral performance compared with the TD group, particularly under the distraction. The ADHD group exhibited significantly higher level of prefrontal activation than did TD children. The activity level was positively correlated with the severity of ADHD symptoms. These results suggest that the impairment in the inhibition of distraction is responsible for the working memory deficits observed in ADHD children. Inefficient processing in the prefrontal cortex appears to underlie such deficits.