Changes in the second messenger cyclic AMP during development may underlie motoric symptoms in attention deficit/hyperactivity disorder (ADHD)

Abstract

The transitions that occur in the ascending dopamine systems between childhood and adulthood parallel the emergence, course, and severity of attention-deficit hyperactivity disorder (ADHD) symptoms. Behaviorally, rats are more active in open field during periadolescence, and activity levels decline by 50% in males by adulthood. This peak in behavior parallels a transient overproduction in D1 and D2 dopamine receptors that occurs at puberty in rat striatum (STR) and prefrontal cortex (PFC), followed by a decline in receptor density into adulthood. While tempting to speculate that receptor density plays a role in the waning of ADHD symptoms, receptor overproduction does not occur in the nucleus accumbens (NA), which demonstrates only a modest rise in receptor density (10-20%). Given the importance of the accumbens in locomotor activity, an alternative explanation for increased activity was sought. The second messenger system cyclic adenosine monophosphate (cAMP) has classically been associated with dopamine receptors. The results of these studies demonstrate that cAMP accumulation in the accumbens and the STR parallel the observed rise and fall in activity levels in rats. At puberty, basal cAMP levels are 35% higher relative to adulthood in male accumbens, while a modest 7% change was observed in STR. Forskolin-stimulated cAMP was 240-300% higher in STR and accumbens at puberty before declining with maturation. These findings suggest that, the adolescent dopamine system has a much higher 'tone' relative to adults. However, pharmacological responsiveness of cAMP to D1 or D2 stimulation demonstrates an overall blunted response during puberty relative to adulthood. This finding is consistent with a hyposensitivity to stress and pharmacological agents at puberty in animals that are in a hyperdopaminergic state. These findings of combined elevated cAMP accumulation and reduced cAMP sensitivity during adolescence have clinical implications for hypothesized mechanism and course of ADHD and its treatment. The maturational decline in cAMP activity may explain why this disorder recedes, while, simultaneously cAMP becomes more responsive to D1 and D2 receptor stimulation in adulthood.