Hypodopaminergic and hypernoradrenergic activity in prefrontal cortex slices of an animal model for attention-deficit hyperactivity disorder — the spontaneously hypertensive rat

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Abstract

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.

Introduction

Attention-deficit hyperactivity disorder (ADHD) is a childhood psychiatric disorder characterized by the presence of symptoms in three domains; inattention, impulsivity and motor overactivity [9]. These symptoms have been suggested to be due to a combination of alerting and executive control deficits involving the prefrontal cortex [2], [36]. Compared with normal controls, children with ADHD were slower, more inaccurate in a visual sustained attention task, more impulsive, displayed a deficit in response inhibition, were less responsive to feedback and showed less perceptual sensitivity and stability of performance, resulting in a marked decrease in vigilance over time [9], [37]. While several inconsistencies exist across studies, evidence supports dysfunction of fronto-striatal neuronal circuits that are regulated by dopaminergic and noradrenergic afferents with resultant executive deficits in cognitive functioning [9], [38].

Motor hyperactivity is one of the most striking abnormalities of ADHD. A possible explanation for the motor hyperactivity appears to be deficient inhibitory control of cortico–striatal–pallidal–thalamic–cortical neural circuits [18]. ADHD children have significantly reduced intracortical inhibition compared with healthy controls [18]. The most frequently prescribed drugs, methylphenidate (ritalin) and d-amphetamine, are highly effective in alleviating all three major symptoms of ADHD. These drugs are psychostimulants, they inhibit reuptake and stimulate release of dopamine and/or norepinephrine thereby increasing the temporal and spatial presence of dopamine and norepinephrine at postsynaptic receptors [23]. In all ADHD children tested, transcranial magnetic stimulation revealed that methylphenidate treatment significantly enhanced intracortical inhibition [18]. Methylphenidate-induced improvements in working memory performance in normal volunteers occurred with task-related reductions in regional cerebral blood flow in the prefrontal cortex and posterior parietal cortex [17]. Stimulants were shown to be equally effective in reducing motor activity and reaction time and improving performance on cognitive tests in ADHD and normal children [22].

Section snippets

Dopaminergic and noradrenergic modulation of transmission through prefrontal cortex circuits

Noradrenergic and dopaminergic systems exert distinct modulatory actions on the transfer of information through neural circuits that connect the thalamus, prefrontal cortex, and basal ganglia neurons. Electrical stimulation of mesocortical dopaminergic neurons located in the ventral tegmental area of the midbrain inhibited spontaneous activity of layer III–VI neurons of the prefrontal cortex [39]. The prefrontal cortex receives excitatory glutamatergic innervation from the dorsomedial nucleus

Rat model for attention-deficit hyperactivity disorder

Motor hyperactivity is one of the most striking abnormalities of ADHD. However, for an animal model to be of value in determining the underlying neurotransmitter disturbances of ADHD, it has, in addition, to mimic the other two major behavioral characteristics of ADHD, namely, impulsiveness and an inability to sustain attention. An animal model for ADHD cannot be expected to accurately reflect all three major symptoms of ADHD. At best, an animal model can provide clues to the underlying

Evidence for hypodopaminergic activity in prefrontal cortex of SHR

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 [4], [12], [13], [24], [25], [26], [27], [28]. The deficiency in electrically stimulated release of DA was not restricted to adult SHR (12–14 weeks old) but was also observed in caudate slices obtained from prepubertal SHR (4 weeks old)

Evidence for hypernoradrenergic activity in prefrontal cortex of SHR

If the monoamine vesicle transporter were the cause of the postulated dopamine deficiency in SHR, then we would expect norepinephrine release to be similarly affected, since both noradrenergic and dopaminergic terminals use the same monoamine vesicle transporter (VMAT2) to transfer monoamines from the cytoplasm into vesicles [24], [35]. We found that neither the electrically stimulated release of norepinephrine nor the 25 mM K+ evoked release of norepinephrine from prefrontal cortex slices of

Conclusion

While electrically stimulated release of dopamine appears to be decreased in prefrontal cortex of SHR, the noradrenergic system appears to be under less inhibitory control than in WKY, suggesting hypodopaminergic and hypernoradrenergic activity in prefrontal cortex of SHR compared with WKY. 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

Acknowledgements

This research was supported by the University of Cape Town, Wilfred Cooper Trust, Nellie Atkinson Fund and the South African Medical Research Council.

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