Pathophysiology --what's actually going on in the brain?
May 21, 2015 at 01:37 PM | categories: physiology, adhd
Contents
1 Theories
Most drugs used to treat hyperactivity have action at the dopamine transporter (DAT) and norepinephrine transporter (NET), indirectly increasing the concentration of synaptic and extrasynaptic catecholamines dopamine (DA) and norepinephrine (NE) [7, 8]. Dysregulation of DA and NE circuits has been postulated as the major pathophysiology of attention-deficit/hyperactivity disorder (ADHD) [1, 4]. Through neuromodulation of fronto–striatal–cerebellar circuits, both DA and NE have critical roles in prefrontal-dependent executive functions thought to underlie clinical symptoms of ADHD, and are a key target for pharmacological manipulation [5].
Most studies looking at DAT and DA receptor densities are restricted to the striatum because of the extremely high density there, and the use of radiotracers with low affinity. Very few studies measure receptor densities in prefrontal cortex, which is more often implicated in the deficits found in ADHD [2]. Berridge and Devilbiss [3] used microdialysis to demonstrate that low, and clinically relevant methylphenidate (MPH) doses preferentially increase extracellular catecholamines in the prefrontal cortex relative to subcortical regions.
As DAT is a major target for ADHD stimulant medications, and medication-naïve ADHD subjects have reduced levels of DAT, DA D2 and D3 receptor availability in subcortical regions (including nucleus accumbens (NAcc), caudate nucleus, and midbrain) [9–11], whereas ADHD patients who had previous medication history showed an increased DAT density [6], it seems long-term treatment with MPH causes long-term changes in DAT and DA receptor expression. Possible alterations to endogenous DA levels in ADHD are likely to trigger complex pre- and post-synaptic compensatory changes to restore balance in the system, which may include changes in DA synthesis, release, receptor sensitivity, and neuronal responsiveness [5]. In order to better understand the DA dysfunction underlying ADHD, abnormal markers of DA signaling need to be understood in the presence of powerful counteracting regulatory influences.
- ADHD
- attention-deficit/hyperactivity disorder
- DAT
- dopamine transporter
- DA
- dopamine
- MPH
- methylphenidate
- NAcc
- nucleus accumbens
- NET
- norepinephrine transporter
- NE
- norepinephrine
References
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