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.