Repeated nicotine administration robustly increases bPiDDB inhibitory potency at α6β2-containing nicotinic receptors mediating nicotine-evoked dopamine release

Andrew M. Smith, Marharyta Pivavarchyk, Thomas E. Wooters, Zhenfa Zhang, Guangrong Zheng, J. Michael McIntosh, Peter A. Crooks, Michael T. Bardo, Linda P. Dwoskin

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

The novel nicotinic receptor (nAChR) antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), and its chemically reduced analog, r-bPiDDB, potently inhibit nicotine-evoked dopamine (DA) release from rat striatal slices. Since tobacco smokers self-administer nicotine repeatedly, animal models incorporating repeated nicotine treatment allow for mechanistic evaluation of therapeutic candidates following neuroadaptive changes. The current study determined the ability of bPiDDB, r-bPiDDB and α-conotoxin MII (α-CtxMII), a peptide antagonist selective for α6β2-containing nAChRs, to inhibit nicotine-evoked [3H]DA release from striatal slices from rats repeatedly administered nicotine (0.4mg/kg for 10 days) or saline (control). Concomitant exposure to maximally effective concentrations of r-bPiDDB (1nM) and α-CtxMII (1nM) resulted in inhibition of nicotine-evoked [3H]DA release no greater than that produced by either antagonist alone, suggesting that r-bPiDDB inhibits α6β2-containing nAChRs. Repeated nicotine treatment increased locomotor activity, demonstrating behavioral sensitization. Concentration-response curves for nicotine-evoked [3H]DA release were not different between nicotine-treated and control groups. Maximal inhibition for α-CtxMII was greater following repeated nicotine compared to control (Imax=90% vs. 62%), with no change in potency. bPiDDB was 3-orders of magnitude more potent in inhibiting nicotine-evoked [3H]DA release in nicotine-treated rats compared to control rats (IC50=5pM vs. 6nM), with no change in maximal inhibition. Neither a shift to the left in the concentration response nor a change in maximal inhibition was observed for r-bPiDDB following repeated nicotine. Thus, repeated nicotine treatment may differentially regulate the stoichiometry, conformation and/or composition of α6β2-containing nAChRs mediating nicotine-evoked striatal DA release. Therefore, bPiDDB and r-bPiDDB appear to target different α6β2-containing nAChR subtypes.

Original languageEnglish
Pages (from-to)402-409
Number of pages8
JournalBiochemical Pharmacology
Volume80
Issue number3
DOIs
StatePublished - Aug 2010

Bibliographical note

Funding Information:
The research reported was supported by NIH grants U19 DA17548, R01 MH53631, T32 DA16176 and F31 DA023853 . The University of Kentucky holds patents on bPiDDB and r-bPiDDB. A potential royalty stream to L.P.D. and P.A.C. may occur consistent with University of Kentucky policy.

Keywords

  • Dopamine release
  • Nicotine
  • Nicotinic acetylcholine receptor
  • Nicotinic receptor antagonist
  • Smoking cessation

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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