Neuronal nicotinic receptor agonists for the treatment of attention-deficit/hyperactivity disorder: focus on cognition

Abstract

Attention deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed neurobehavioral disorder in children and adolescents, and in about half of these patients, significant symptomology continues into adulthood. Although impulsivity and hyperactivity are the most salient features of ADHD, cognitive deficits, particularly impairments in attention and executive function, are an important component, particularly in adolescents and adults, with over 90% of adults seeking treatment for ADHD manifesting cognitive dysfunction. Currently available medications treat the core ADHD symptoms but typically do not adequately address cognitive aspects of ADHD, underscoring the need for new therapeutics. Dopamine and norepinephrine are hypothesized to be particularly important in ADHD, but there is emerging evidence that cholinergic neurotransmission, particularly involving neuronal nicotinic acetylcholine receptors (nAChRs), may play a role in the pathophysiology of ADHD. Nicotine has demonstrated procognitive effects in both humans and experimental animals and has produced signals of efficacy in small proof-of-concept adult ADHD trials. Although adverse effects associated with nicotine preclude its development as a therapeutic, a number of novel nAChR agonists with improved safety/tolerability profiles have been discovered. Of these, ABT-418 and ABT-089 have both demonstrated signals of efficacy in adults with ADHD. Notably, tolerability issues that might be expected of a nAChR agonist, such as nausea and emesis, were not observed at efficacious doses of ABT-089. Further understanding of the effects of novel neuronal nAChR agonists on specific aspects of cognitive functioning in ADHD is required to assess the full potential of this approach.

Figure 1

Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels, each composed of five subunits surrounding a cation pore. The cartoons on the left provide a view of the receptor from above (looking down into the channel pore), whereas the illustration on the right provides a cut-away side view. In vertebrates, 12 subunits have been identified: nine α subunits (α2 -α10) and three β subunits (β2 -β4). However, not all possible subunit combinations form functional receptors. For example, β subunits can only form functional receptors if combined with α subunits, and α2 -α6 subunits require the presence of β2 or β4 subunits, with the further requirement that α5-containing receptors have additional α subunits. α4β2-containing (designated α4β2*) nAChRs are the most common subtype in brain and have high affinity for nicotine. The example in the figure contains only α4 and β2 subunits, but there is also evidence that some α4β2* receptors contain other subunits as well (e.g., α6 or α5) which can alter their pharmacological and electrophysiological properties. α7 - α10 subunits do not need to be combined with β subunits to form functional nAChRs. The most common of these subunits is α7, which appears to form a homopentomeric nAChR in vivo. This α7 nAChR is the second most abundant nAChR in brain and has low affinity for nicotine but higher permeability to Ca²⁺ and faster desensitization kinetics than the α4β2* nAChR.