Platelet Alpha₂-Adrenergic Receptor Binding and the Effects of <i>d</i>-Amphetamine in Boys with Attention Deficit Hyperactivity Disorder

Abstract

Presynaptic inhibitory alpha-adrenergic receptors are involved in regulating the release of norepinephrine (NE) through a negative feedback mechanism mediated by NE. Increased alpha₂-adrenergic receptor activity suggests decrease NE release and activity, while decreased alpha₂-adrenergic activity suggests increase NE release and activity. A large body of evidence suggests the involvement of a disturbance in NE activity in the pathophysiology of attention deficit hyperactivity disorder (ADHD) in childhood. Platelet alpha₂-adrenergic receptor binding was compared in 23 boys aged 7–12 with the diagnosis of ADHD and 11 normal controls. The ADHD boys tended to have lower levels of alpha₂-binding than controls. The administration of d-amphetamine in a double-blind placebo-controlled crossover design did not have any effect on alpha₂-receptor binding in ADHD boys. Nonresponders to d-amphetamine had the lowest alpha₂-receptor binding compared to responders and controls. These findings suggest a normal alpha₂-adrenergic activity in ADHD boys responders to d-amphetamine and a possible increase in NE release in ADHD boys nonresponders to d-amphetamine due to decreased alpha₂-adrenergic receptors.

Prenatal cocaine exposure enhances responsivity of locus coeruleus norepinephrine neurons: Role of autoreceptors

“…In fact, clonidine, which decreases NE activity, has been reported to be of benefit in ADHD and is now in a Phase III clinical trial for treatment of ADHD (http://clinicaltrials.gov/show/NCT00031395). Our evidence suggests that a decrease in α2-adrenergic autoreceptor control of NE activity underlies noradrenergic hyperfunction in our rat model of prenatal cocaine, so it is interesting that a similar deficit appears to occur in the spontaneously hypertensive rat model of ADHD (Russell, 2002) and that a decreased density and decreased affinity of binding to α2-adrenergic sites have been reported in ADHD (Shekim et al, 1994;Deupree et al, 2006). Moreover, there is evidence supporting association and linkage of α2A-adrenergic receptor gene polymorphisms with ADHD (Park et al, 2005).…”

Possible involvement of alpha‐2A adrenergic receptors in attention deficit hyperactivity disorder: Radioligand binding and polymorphism studies

“…However, the significant correlation with severity among affected boys was negative. One earlier study has shown that ADHD boys tended to have a lower alpha-2 adrenergic receptor density [Shekim et al, 1994]. Nevertheless these results indicate the possibility of a polymorphism in the regulatory regions of the alpha-2 adrenergic receptor gene associated with ADHD.…”

“…Further studies which include gene function phenotypes as well as more complete behavioral assessments may help define the phenotypes that are most affected by a given candidate gene. Radioligand binding assays of the alpha-2A adrenergic receptor on human platelets are commonly used to study the involvement of the noradrenergic system in various psychiatric disorders including depression, schizophrenia, and ADHD [Katona et al, 1989;Karege et al, 1992;Piletz et al, 1993;Shekim et al, 1994;Maes et al, 1999;Gurguis et al, 1999a;Odagaki and Koyama, 2002]. Previous studies have noted the problems associated with the day-to-day variability of this assay as well the variability of the binding parameters among subjects [Reimann et al, 1987].…”

“…The human platelet has been used extensively as a model in psychiatry Shekim et al, 1984Shekim et al, , 1990Kanof et al, 1988;Hrdina et al, 1995;Sheline et al, 1995;Gurguis et al, 1999b,c] because changes in receptor characteristics of platelets can be used as an indirect marker of neurotransmitter receptor alterations in psychiatric disorders [Wirz-Justice, 1988]. In a study with 23 boys with ADHD and 11 age-matched controls, the ADHD boys tended to have a lower alpha-2 adrenergic receptor density suggesting that the characteristics of platelet alpha-2 adrenergic receptors may be different in ADHD patients as compared to controls [Shekim et al, 1994]. Interestingly, the non-responders to d-amphetamine had the lowest alpha-2 adrenergic receptor densities.…”

Quantification of [11C]yohimbine Binding to α2 Adrenoceptors in Rat Brain in vivo

“…Amphetamine is known to not alter the binding of yohimbine to peripheral α 2 R on platelets, as reported for humans. 17 Therefore, we performed plasma ultrafiltration to test the hypothesis that amphetamine does not affect plasma protein binding as reflected in measures of the plasma-free fraction, in support of the assumption underlying the Inhibition plot that the values of V ND are unchanged.…”