r-bPiDI, an α6β2* Nicotinic Receptor Antagonist, Decreases Nicotine-Evoked Dopamine Release and Nicotine Reinforcement

Authors

Joshua S. Beckmann, University of KentuckyFollow
Andrew C. Meyer, University of Kentucky
Marharyta Pivavarchyk, University of Kentucky
David B. Horton, University of KentuckyFollow
Guangrong Zheng, University of Arkansas for Medical Sciences
Andrew M. Smith, University of Kentucky
Thomas E. Wooters, University of Kentucky
J. Michael McIntosh, University of Utah
Peter A. Crooks, University of Arkansas for Medical SciencesFollow
Michael T. Bardo, University of KentuckyFollow
Linda P. Dwoskin, University of KentuckyFollow

Abstract

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 [³H]nicotine and [³H]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 [³H]nicotine or [³H]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.

Document Type

Article

Publication Date

2015

Notes/Citation Information

© Springer Science+Business Media New York 2015

Digital Object Identifier (DOI)

https://doi.org/10.1007/s11064-015-1680-4

Funding Information

This research was supported by NIH Grant DA017548, DA016176, TR000117, GM103801 and GM48677.

Repository Citation

Beckmann, Joshua S.; Meyer, Andrew C.; Pivavarchyk, Marharyta; Horton, David B.; Zheng, Guangrong; Smith, Andrew M.; Wooters, Thomas E.; McIntosh, J. Michael; Crooks, Peter A.; Bardo, Michael T.; and Dwoskin, Linda P., "r-bPiDI, an α6β2* Nicotinic Receptor Antagonist, Decreases Nicotine-Evoked Dopamine Release and Nicotine Reinforcement" (2015). Psychology Faculty Publications. 250.
https://uknowledge.uky.edu/psychology_facpub/250