TC-6683

Studies performed in healthy smokers have documented a diminished responsiveness to tussive challenges, and several lines of experimental evidence implicate nicotine as an antitussive component in both cigarette smoke and the vapors generated by electronic cigarettes (eCigs). We set out to identify the nicotinic receptor subtype involved in the antitussive actions of nicotine and to further evaluate the potential of nicotinic receptor-selective agonists as cough-suppressing therapeutics. We confirmed an antitussive effect of nicotine in guinea pigs. We additionally observed that the alpha-4 beta-2 (α ₄ β ₂)-selective agonist Tc-6683 was without effect on evoked cough responses in guinea pigs, while the α ₇-selective agonist PHA 543613 dose-dependently inhibited evoked coughing. We subsequently describe the preclinical evidence in support of ATA-101, a potent and highly selective (α ₇) selective nicotinic receptor agonist, as a potential candidate for antitussive therapy in humans. ATA-101, formerly known as Tc-5619, was orally bioavailable and moderately central nervous system (CNS) penetrant and dose-dependently inhibited coughing in guinea pigs evoked by citric acid and bradykinin. Comparing the effects of airway targeted administration versus systemic dosing and the effects of repeated dosing at various times prior to tussive challenge, our data suggest that the antitussive actions of ATA-101 require continued engagement of α ₇ nicotinic receptors, likely in the CNS. Collectively, the data provide the preclinical rationale for α ₇ nicotinic receptor engagement as a novel therapeutic strategy for cough suppression. The data also suggest that α ₇ nicotinic acetylcholine receptor (nAChR) activation by nicotine may be permissive to nicotine delivery in a way that may promote addiction. SIGNIFICANCE STATEMENT: This study documents the antitussive actions of nicotine and identifies the α₇ nicotinic receptor subtype as the target for nicotine during cough suppression described in humans. We additionally present evidence suggesting that ATA-101 and other α₇ nicotinic receptor-selective agonists may be promising candidates for the treatment of chronic refractory cough.

The entire cingulate cortex is engaged in the structure/function abnormalities found in attention-deficit/hyperactivity disorder (ADHD). In ADHD, which is the most common developmental disease, impaired impulse control and cognition often trace to anterior midcingulate cortex (aMCC) in Go/No-go tests, decoding and reading, the Stroop Color and Word Test, and the Wisconsin Card Sorting Test (WCST), with volume deficits in anterior cingulate cortex (ACC) and posterior midcingulate cortex (pMCC). Volumes in pMCC correlate positively with the WCST and negatively with total and nonperseverative errors on the WCST. Activation and connectivity on N-back tests show connections for high and low spatial working memory, but patients have increased activation in PCC and decreased connectivity between MCC and PCC for high load. Students struggle in class due to malfunctioning aMCC, pregenual anterior cingulate cortex (pACC), and dorsal posterior cingulate cortex (dPCC), and to core deficits in response/task switching in aMCC. Gene mutations are found in the DA transporter and DA4 and DA5 receptors. Methylphenidate decreases hyperactivity in aMCC. The DA system is controlled by cholinergic receptors in the daMCC and genetics show nAChR mutations in alpha 3, 4, and 7 receptors. At 25 years, a modified Eriksen flanker/No-go task and voxel-based morphometry (VBM) show prenatal smoking, lifetime smoking at 13 years, and novelty seeking. Prenatal exposure to nicotine exhibits weaker responses in aMCC during cognitive tasks for hyperactivity/impulsiveness but not inattention. AZD1446 (ɑ4β2 nAChR agonist) improves the Groton Maze task due to high nAChR in dPCC/RSC engaged in spatial orientation. Environmental factors associated with childhood ADHD relate to pesticides, organochlorine, and air pollutants. Network connection segregation shows increased amygdala local nodal, but decreased ACC and PCC connections, reflecting emphasis on local periamygdala connections at the expense of cortical connections. Thus, ADHD children/adolescents respond impulsively to the significance of stimuli without having cortical inhibition. Finally, controls show negative relationships between aMCC and the default mode network, and ADHD compromises this relationship, showing decreased connectivity between ACC and precuneus/PCC.