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 language | English |
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Pages (from-to) | 402-409 |
Number of pages | 8 |
Journal | Biochemical Pharmacology |
Volume | 80 |
Issue number | 3 |
DOIs | |
State | Published - 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