Neurobiology of Attention Deficit Disorder With Hyperactivity: Where Have We Come in 50 Years?

doi:10.1097/00004583-198709000-00011

Journal of the American Academy of Child & Adolescent Psychiatry

Volume 26, Issue 5, September 1987, Pages 676-686

https://doi.org/10.1097/00004583-198709000-00011 Get rights and content

Over 20 neuropharmacological agents have been used for the study and treatment of children with Attention Deficit Disorder with Hyperactivity since Charles Bradley first described the effects of benzedrine in 1937, now 50 years ago. Although an array of drugs are superior to placebo, the stimulants are still the treatment of choice. The large number of efficacious drugs do not support any single neurotransmitter defect hypothesis, and no current model can account for the abundance of “positive” findings. The most promising areas for research at this time appear to be in-depth studies of response to stimulants and more physiological studies using brain imaging techniques.

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Prediction profiling may be useful, since the pattern of results may not only guide the clinician as to which medication (or not) to prescribe, but could also serve to monitor the progress of the selected medication.10 Despite the absence of universally accepted (gold-standard) change with response criteria, several previous reviews summarized the findings on behavioral and neurochemical variables which may predict treatment response and have suggested that only weak associations exist between either behavioral measures or neurochemistry and drug response in ADHD.11,12 Interestingly several studies pointed out that neurobiological differences may exist between subjects with ADHD who did not respond to MPH and those who did.
Attention Deficit Hyperactivity Disorder (ADHD) is one of the most prevalent mental disorders of childhood, which often continues into adulthood. Methylphenidate is one the most commonly used medication to treat ADHD, however up to 30% of patients do not respond to it.
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A state of low dopaminergic activity has been implicated in attention-deficit/hyperactivity disorder (ADHD). The clinical symptoms of ADHD include inattention, impulsivity and hyperactivity, as well as impaired learning; dopaminergic modulation of the functions in the hippocampus is important to both learning and memory. To determine dopamine receptor (DR) density in a well-established animal model for ADHD, we quantified the dopamine D5 receptors in the hippocampus in the spontaneously hypertensive rat. We used immunofluorescence microscopy and immunogold electron microscopy to quantify the dopamine D5 receptor density on CA1 pyramidal cell somas and dendrites and dendritic spines in the stratum radiatum and stratum oriens. The density of the dopamine D5 receptors was significantly lower in the cytoplasm of pyramidal cell somas in the spontaneously hypertensive rat compared to the control, indicating a reduced reservoir for insertion of receptors into the plasma membrane. DRs are important for long-term potentiation and long-term depression, hence the deficit may contribute to the learning difficulties in individuals with the diagnosis of ADHD.
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The largest group of brain noradrenergic neurons is in the brainstem locus coeruleus (LC), which sends widespread projections to forebrain areas and is the only source of NE in the hippocampus and neocortex (Berridge and Waterhouse, 2003; Foote et al., 1983; Ungerstedt, 1971). Psychostimulants are known to improve hyperactivity, impulsivity and inattentiveness in attention deficit/hyperactivity disorder (ADHD) by stimulating NE and dopamine (DA) neurotransmission (Biederman and Spencer, 1999; Zametkin and Rapoport, 1987), but they are also effective at improving attention and other cognitive processes in healthy individuals (Mohamed and Sahakian, 2011; Sahakian and Morein-Zamir, 2011). ADHD drugs such as methylphenidate and amphetamines have recently gained popularity as cognitive enhancers and their use by the “non-clinical” population has grown accordingly (Greely et al., 2008).
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REVIEW ARTICLENeurobiology of Attention Deficit Disorder With Hyperactivity: Where Have We Come in 50 Years?

J. Pediat.

J. Pediat.

This Journal.

This Journal.

Psychiat. Clin North Amer.

This Journal.

Biochem. Pharmacol.

This Journal.

Biochem. Behav.

Developm. Biol.

This Journal.

Brain Res.

Compr. Psychiat.

Brain Res. Bull.

Psych, Res.

This Journal.

Brain Res.

Neuropharmacology.

Brain. Res.

Biol. Psych.

J. Pediat.

Lancet

This Journal

This Journal.

The release of endogenous norepinephrine and dopamine from cerebral cortex by amphetamine

J. Pharmacol. Exp. Ther.

Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle

J. Neuroscience.

A review of stimulant drug research with hyperactive children

J. Child Psychol. Psychiat.

The effect of pyridoxine hydrochloride on blood serotonin and pyridoxal phosphate contents -in hyperactive children

Pediatrics.

The behavior of children receiving Benzedrine

Amer. J. Psychiat.

Urinary 3-methoxy-4-hydroxyphenylglycol and homovanillic acid response to d-amphetamine in hyperactive children

Biol. Psychiat.

Aggression, Suicide and serotonin: relationships to CSF amine metabolites

Amer. J. Psychiat.

Plasma levels of d-amphetamine in hyperactive children

Psychopharmacology

D & L amphetamine stereo-isomers: comparative potencies in affecting the firing of central dopaminergic and nor adrenergic neurons

Psychopharm. Comm.

Hyperactive children's event-related potentials fail to support underarousal and maturational-lag-theories

Arch. Gen. Psychiat.

Stimulants

Computed tomographic brain scanning in children with developmental Neuropsychiatric disorders

This Journal

Frontal lobe disinhibition in attention deficit disorder

Child Psychiat. Hum. Develpm.

Effects of meth-Maze performance in emotionally disturbed children

J. Consult. Clin. Psychol.

Treatment of hyperactivity with desipramine: plasma drug concentration, cardiovascular effects, plasma and urinary catecholamine levels, and clinical response

Clin. Pharm. Ther.

Specific learning disabilities: an attentional deficit syndrome

Plasma free and total tryptophan, blood serotonin and the hyperactivity syndrome: no evidence for serotonin deficiency hypothesis

Biol. Psychol.

Imaging opiate receptors in the human brain by positron tomography

J. Comp. Assisted Tomogr.

Comparative effects of pemoline, amfoelic acid, and amphetamine on dopamine uptake and release in vitro on brain 3, 4-dihydroxy-phenylacetic acid concentration on spiperone-treated rats

J. Pharm. Pharmacol.

Comparative effects of methylphenidate and thioridazine in hyperkinetic children

Arch. Gen. Psychiat.

A comparison of the vascular dopamine receptor with other dopamine receptors

Annu. Rev. Pharmacol. Toxicol.

REVIEW ARTICLE
Neurobiology of Attention Deficit Disorder With Hyperactivity: Where Have We Come in 50 Years?