COMMENTARY

Nicotinic Attention-Deficit/Hyperactivity Disorder Treatment Edward D. Levin

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icotine is not native to the human nervous system, but nicotinic receptors certainly are. Nicotine is the prototypic agonist for one of the two principal subtypes of acetylcholine receptors. Nicotinic receptors are critical for a wide variety of neurobehavioral functions, including muscle movement (with actions in the neuromuscular junction), sympathetic and parasympathetic responsivity (with actions in the autonomic ganglia), cognitive function (with actions in the hippocampus and frontal cortex), emotional function (with actions in the amygdala), and reward (with actions in the ventral tegmental area). Nicotine is notorious as the primary (but not only) psychoactive chemical in tobacco. Nicotine self-administration is an essential component of tobacco addiction. However, like other drugs with abuse liability, such as opiates and benzodiazepines, nicotinic drugs may have useful therapeutic applications. The article by Potter et al. (1) in this issue describes the efficacy of a novel nicotinic agonist AZD3480 in reducing an array of cognitive and emotional symptoms of attention-deficit/hyperactivity disorder (ADHD). It is well known that people with psychopathology, including schizophrenia, depression, and ADHD, have much higher rates of tobacco smoking than the general population, two to three times as much (2). It may be the case that people with these conditions are more easily addicted to smoking. However, it has also been found that nicotine does attenuate some of the neurobehavioral impairments seen in these conditions and people with them may be self-medicating for cognitive and affective dysfunction, albeit in a particularly deadly fashion. This raises some important issues in both the goal of smoking cessation and development of new more effective therapeutic treatments for these conditions. Given that there are demonstrable therapeutic effects of nicotine, nicotinic treatment may be useful in both providing a new line of therapeutic treatment and an effective way of having people with schizophrenia, depression, and ADHD to overcome tobacco addiction. Particularly evident is nicotine-induced improvement of attentional function. Over the last couple of decades, nicotine has been shown repeatedly in a variety of studies in both animal models and clinical experiments to significantly improve attention and reverse attentional dysfunction. A variety of pharmaceutical companies and academic labs have been testing novel nicotinic ligands for treatment of attentional impairment seen in ADHD and other syndromes with cognitive impairment, principally Alzheimer’s disease and schizophrenia. Nicotine itself given via the nicotine skin patch has been shown to be efficacious in reducing the attentional impairment and other symptoms of ADHD (3–6). When delivered by the skin patch, nicotine has low

abuse liability and is well tolerated. More selective nicotinic agonists for the α4β2 and α7 nicotinic receptors have also been shown to improve attentional performance and reverse attentional dysfunction in animal models (7–9) and there is evidence that a nicotinic agonist other than nicotine improves symptoms of ADHD in adults (10). In the article in this issue, Potter et al. (1) report that the novel nicotinic agonist AZD3480 (TC-1734) significantly improved ADHD symptoms in a placebo-controlled double-blind study. This is an important advance in developing nicotinic treatments for cognitive dysfunction. These may provide an added modality for improving cognitive function in people with ADHD with the great possible added benefit of helping them to quit selfmedicating with tobacco. The author has received research funding from AstraZeneca and Targacept, Inc. 1. Potter AS, Dunbar G, Mazzulla E, Hosford D, Newhouse PA (2014): AZD3480, a novel nicotinic receptor agonist, for the treatment of attention-deficit/hyperactivity disorder in adults. Biol Psychiatry 75: 207–214. 2. Newhouse P, Singh A, Potter A (2004): Nicotine and nicotinic receptor involvement in neuropsychiatric disorders. Curr Top Med Chem 4: 267–282. 3. Levin ED, Conners CK, Silva D, Canu W, March J (2001): Effects of chronic nicotine and methylphenidate in adults with attention deficit/ hyperactivity disorder. Exp Clin Psychopharmacol 9:83–90. 4. Levin ED, Conners CK, Sparrow E, Hinton SC, Erhardt D, Meck WH, et al. (1996): Nicotine effects on adults with attention-deficit/hyperactivity disorder. Psychopharmacology (Berl) 123:55–63. 5. Potter AS, Newhouse PA (2004): Effects of acute nicotine administration on behavioral inhibition in adolescents with attention-deficit/ hyperactivity disorder. Psychopharmacology (Berl) 176:182–194. 6. Shytle RD, Silver AA, Wilkinson BJ, Sanberg PR (2002): A pilot controlled trial of transdermal nicotine in the treatment of attention deficit hyperactivity disorder. World J Biol Psychiatry 3:150–155. 7. Hahn B, Sharples CG, Wonnacott S, Shoaib M, Stolerman IP (2003): Attentional effects of nicotinic agonists in rats. Neuropharmacology 44: 1054–1067. 8. Rezvani AH, Kholdebarin E, Brucato FH, Callahan PM, Lowe DA, Levin ED (2009): Effect of R3487/MEM3454, a novel nicotinic alpha7 receptor partial agonist and 5-HT3 antagonist on sustained attention in rats. Prog Neuropsychopharmacol Biol Psychiatry 33:269–275. 9. Sydserff S, Sutton EJ, Song D, Quirk MC, Maciag C, Li C, et al. (2009): Selective alpha7 nicotinic receptor activation by AZD0328 enhances cortical dopamine release and improves learning and attentional processes. Biochem Pharmacol 78:880–888. 10. Wilens TE, Biederman J, Spencer TJ, Bostic J, Prince J, Monuteaux MC, et al. (1999): A pilot controlled clinical trial of ABT-418, a cholinergic agonist, in the treatment of adults with attention deficit hyperactivity disorder. Am J Psychiatry 156:1931–1937.

From the Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina. Address correspondence to Edward D. Levin, Ph.D., Duke University Medical Center, Department of Psychiatry and Behavioral Sciences, Triangle Biotechnology Center, Neurobehavioral Research Laboratory, DUMC Box 104790, 323 Foster St, Durham, NC 27710; E-mail: [email protected] Received and accepted Nov 27, 2013.

0006-3223/$36.00 http://dx.doi.org/10.1016/j.biopsych.2013.11.024

BIOL PSYCHIATRY 2014;75:174 & 2014 Society of Biological Psychiatry

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