Targeting the Nicotinic Cholinergic System to Treat Attention-Deficit/Hyperactivity Disorder: Rationale and Progress to Date

Abstract

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common, chronic neurobehavioral disorder related to clinically significant levels of inattention, hyperactivity and/or impulsivity. ADHD begins in childhood and symptoms persist into adulthood for the majority of those with the disorder. Associated features of ADHD include emotion dysregulation and cognitive impairments which contribute to the considerable functional impairments in this disorder. Current approved treatments are reasonably effective however a significant need remains for new pharmacotherapies, both for individuals who do not achieve a full therapeutic response and for symptoms that are under-treated including cognition and emotion regulation. The striking relationship between ADHD and cigarette smoking and the known effects of nicotine on cognition has spurred research into the therapeutic potential of nicotinic agents for ADHD. Although there are no approved medications for ADHD that target nicotinic acetylcholine receptor (nAChR) function, results from many trials of nicotinic drugs are available and reviewed in this article. ADHD symptoms were reduced in the majority of published studies of nicotine and novel α4β2 nicotinic agonists in adult ADHD. The drugs were generally well tolerated, with mild to moderate side effects reported, which were largely consistent with cholinergic stimulation and included nausea, dizziness, and gastrointestinal distress. Within-subject crossover study designs were used in the majority of positive studies. This design may be particularly useful in ADHD trials because it minimizes variability in this notoriously heterogeneous diagnostic group. In addition, many studies found evidence for a beneficial effect of nicotinic stimulation on cognitive and emotional domains. Thus, targeting nAChRs in ADHD appears to have modest clinical benefit in adult ADHD. Continued refinement of nAChR agonists with greater specificity and fewer side effects may lead to even more effective nAChR agonists for ADHD. Future clinical trials in ADHD should include direct measures of neuropsychological performance and emotion regulation.

ADHD symptoms impact smoking outcomes and withdrawal in response to Varenicline treatment for smoking cessation

“…These molecular actions may also explain varenicline’s efficacy in reducing withdrawal, given that nicotine withdrawal is associated with reductions in basal dopamine levels in the striatum (Zhang et al, 2012). Overall, because nicotine has been linked to reduction of ADHD symptoms (Conners et al, 1996; Potter et al, 2014), it is possible that varenicline may contribute to successful decreases smoking in individuals with high HI, partially through an effect on reducing ADHD symptoms in concert with changing smoking behavior. Future research examining ADHD symptom dimensions over the course of varenicline treatment is necessary to shed light on this hypothesis.…”

Causal Factors of Increased Smoking in ADHD: A Systematic Review

“…The self-medication hypothesis is also endorsed by the results obtained with the nicotine analogues bupropion and varenicline (Potter, Schaubhut, & Shipman, 2014;Ferris & Beaman, 1983;Mihalak, Carroll, & Luetje, 2006;Rhodes et al, 2012) which have been successfully applied as smoking cessation aid (Hurt et al, 1997;Aubin et al, 2008). Bupropion showed beneficial effect during treatment of ADHD.…”

Prenatal Alcohol Exposure in Rodents As a Promising Model for the Study of ADHD Molecular Basis

“…Also, it has been demonstrated that perinatal choline supplementation may attenuate alcohol-related behavioral changes by influencing cholinergic systems (Monk et al, 2012). For ADHD, there are evidences that point to a role of the cholinergic system in ADHD cognitive dysfunction (Potter et al, 2006; Sarter and Paolone, 2011) and that emphasize the relevance of the therapeutic potential of nicotinic cholinergic agents for their treatment (Potter et al, 2014). Therefore, it is necessary to develop more enhanced understanding of the nicotinic cholinergic system and its role in ADHD (Childress and Sallee, 2014).…”