r-bPiDI, an α6β2* Nicotinic Receptor Antagonist, Decreases Nicotine-Evoked Dopamine Release and Nicotine Reinforcement.
α6β2* nicotinic acetylcholine receptors (nAChRs) expressed by dopaminergic neurons mediate nicotine-evoked dopamine (DA) release and nicotine reinforcement. α6β2* antagonists inhibit these effects of nicotine, such that α6β2* receptors serve as therapeutic targets for nicotine addiction. The present research assessed the neuropharmacology of 1,10-bis(3-methyl-5,6-dihydropyridin-1(2H)-yl)decane (r-bPiDI), a novel small-molecule, tertiary amino analog of its parent compound, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI). bPiDI was previously shown to inhibit both nicotine-evoked DA release and the reinforcing effects of nicotine. In the current study, r-bPiDI inhibition of [(3)H]nicotine and [(3)H]methyllycaconitine binding sites was evaluated to assess interaction with the recognition binding sites on α4β2* and α7* nAChRs, respectively. Further, r-bPiDI inhibition of nicotine-evoked DA release in vitro in the absence and presence of α-conotoxin MII and following chronic in vivo nicotine administration were determined. The ability of r-bPiDI to decrease nicotine self-administration and food-maintained responding was also assessed. Results show that r-bPiDI did not inhibit [(3)H]nicotine or [(3)H]methyllycaconitine binding, but potently (IC50 = 37.5 nM) inhibited nicotine-evoked DA release from superfused striatal slices obtained from either drug naïve rats or from those repeatedly treated with nicotine. r-bPiDI inhibition of nicotine-evoked DA release was not different in the absence or presence of α-conotoxin MII, indicating that r-bPiDI acts as a potent, selective α6β2* nAChR antagonist. Acute systemic administration of r-bPiDI specifically decreased nicotine self-administration by 75 %, and did not alter food-maintained responding, demonstrating greater specificity relative to bPiDI and bPiDDB, as well as the tertiary amino analog r-bPiDDB. The current work describes the discovery of r-bPiDI, a tertiary amino, α-conotoxin MII-like small molecule that acts as a potent and selective antagonist at α6β2* nAChRs to specifically decrease nicotine self-administration in rats, thus, establishing r-bPiDI as a lead compound for development as a treatment for nicotine addiction.
['Beckmann|Joshua S|JS|', 'Meyer|Andrew C|AC|', 'Pivavarchyk|M|M|', 'Horton|David B|DB|', 'Zheng|Guangrong|G|', 'Smith|Andrew M|AM|', 'Wooters|Thomas E|TE|', 'McIntosh|J Michael|JM|', 'Crooks|Peter A|PA|', 'Bardo|Michael T|MT|', 'Dwoskin|Linda P|LP|']
D000157:Aconitine D000818:Animals D001522:Behavior, Animal D020916:Conotoxins D003342:Corpus Striatum D004298:Dopamine D008297:Male D009538:Nicotine D018733:Nicotinic Antagonists D010847:Picolines D011726:Pyridinium Compounds D017207:Rats, Sprague-Dawley D011978:Receptors, Nicotinic
Nicotine Dopamine Reinforcement Abuse