Methylphenidate-evoked changes in striatal dopamine correlate with inattention and impulsivity in adolescents with attention deficit hyperactivity disorder

Abstract

Abnormal central dopamine (DA) neurotransmission has been implicated in the impulsivity, inattention, and hyperactivity of attention deficit hyperactivity disorder (ADHD). We hypothesized that a pharmacological challenge with methylphenidate (MP) at a therapeutic dose increases extracellular DA concentrations in proportion to the severity of these specific ADHD symptoms. To test this hypothesis, we measured by PET the effect of acute challenge with MP on the availability of striatal binding sites for [¹¹C]raclopride (pB), an index of altered interstitial DA concentration, in nine unmedicated adolescents (1 female, 8 males; age 13.7 ± 1.8 years) with a current diagnosis of ADHD. We estimated the pB of [¹¹C]raclopride for brain dopamine D_2/3 receptors first in a baseline resting condition, and again after an acute challenge with MP (0.3 mg/kg, p.o.), and calculated the percentage change in (%ΔpB) in left and right striatum. On another day, measurements of impulsivity and inattention were performed using a computerized continuous performance test. There was a significant correlation between the magnitude of %ΔpB in the right striatum and the severity of inattention and impulsivity. MP-evoked %ΔpB correlated with standard scores for impulse control (r = 0.68; P = 0.02), attention (r = 0.81; P = 0.005), information processing (r = 0.66; P = 0.02), and consistency of attention, or variability (r = 0.60; P = 0.04). In conclusion, the results link inattention and impulsivity with sensitivity of brain DA receptor availability to an MP challenge, corroborating the hypothesis that MP serves to potentiate decreased DA neurotransmission in ADHD.

Introduction

Most patients with attention deficit hyperactivity disorder (ADHD) benefit from treatment with methylphenidate (MP), irrespective of the etiology of the disorder (Santosh and Taylor, 2000, Weber and Lutschg, 2002). Therapeutic doses of MP increase extracellular dopamine (DA) concentrations in the striatum, suggesting that the impulsivity, inattention, and hyperactivity of ADHD are relieved by pharmacological potentiation of striatal DA neurotransmission (Volkow et al., 2001). However, the effect of psychostimulants on attention is not pathognomic for ADHD: in a study of healthy volunteers, d-amphetamine likewise decreased impulsivity as measured by the Stop task (De Wit et al., 2002). The concentration of the DA metabolite homovanillic acid (HVA) is abnormally low in cerebrospinal fluid of children with ADHD, suggesting that abnormal cerebral DA metabolism is indeed a marker of the ADHD trait (Castellanos et al., 1994, Castellanos et al., 1996a, Shaywitz et al., 1977). Four of five recent SPECT studies showed increased concentration of plasma membrane DA transporters (DAT) in brain of patients with ADHD (Dougherty et al., 1999, Dresel et al., 2000, Krause et al., 2000, Van Dyck et al., 2002). If these transporters are functional, the capacity for re-uptake of extracellular DA must be enhanced. Together, these findings imply that the therapeutic benefits of MP in the treatment of ADHD might be attributed to rectification of abnormally low phasic extracellular DA concentrations.

The availability of DA D_2/3 binding sites for benzamide radioligands in living brain is influenced by competition from endogenous DA (Laruelle, 2000). Thus, the binding potential (pB, B_max/K_d) of a DA receptor radioligand in vivo is proportional to the ratio of bound-to-free radioligand at equilibrium, but reduced by the prevailing competition from endogenous DA. Consequently, in benzamide radioligand imaging studies, the post-psychostimulant decline in receptor availability (%ΔpB) is indicative of the magnitude of the pharmacologically evoked increase in extracellular DA (Endres et al., 1997, Laruelle et al., 1995). Using this paradigm, enhanced d-amphetamine-evoked DA release has been detected in patients with Tourette's syndrome (Singer et al., 2002), a disorder in which the lack of impulse control trait has been correlated with increased DAT binding in a SPECT study (Muller-Vahl et al., 2000). However, there have hitherto been no functional imaging studies of the effects of psychostimulant challenge on DA receptor availability in patients with ADHD. We hypothesized that the magnitude of MP-evoked %ΔpB for [¹¹C]raclopride should be in proportion to the severity of clinical symptoms for ADHD. The Test of Variables of Attention (TOVA) is a widely used computerized continuous performance test for assessing the severity of symptoms in ADHD patients (Aggarwal and Lillystone, 2000, Schatz et al., 2001). Previous reports have showed that the TOVA sensitively differentiates ADHD patients from a control population, and can detect the ameliorative effects of MP on attention and impulse control (Greenberg and Waldman, 1993, Manor et al., 2002a, Manor et al., 2002b). To test our hypothesis, we used positron emission tomography (PET) to measure the pB of [¹¹C]raclopride for striatal dopamine D_2/3 receptors first in a resting baseline condition and again after challenge with a therapeutic dose of MP in adolescent subjects with diagnosis of ADHD, and tested the correlation between the %ΔpB with individual performance of the TOVA.