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.
Funding
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.
Funders | Funder number |
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National Institutes of Health (NIH) | R01 MH53631, F31 DA023853, T32 DA16176 |
National Institute on Drug Abuse | U19DA017548 |
Keywords
- Dopamine release
- Nicotine
- Nicotinic acetylcholine receptor
- Nicotinic receptor antagonist
- Smoking cessation
ASJC Scopus subject areas
- Biochemistry
- Pharmacology