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

doi:10.1016/j.bcp.2010.03.018

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 journal › Article › peer-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 (I_max=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
Pages (from-to)	402-409
Number of pages	8
Journal	Biochemical Pharmacology
Volume	80
Issue number	3
DOIs	https://doi.org/10.1016/j.bcp.2010.03.018
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
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

Access to Document

10.1016/j.bcp.2010.03.018

Cite this

Smith, A. M., Pivavarchyk, M., Wooters, T. E., Zhang, Z., Zheng, G., McIntosh, J. M., Crooks, P. A., Bardo, M. T., & Dwoskin, L. P. (2010). Repeated nicotine administration robustly increases bPiDDB inhibitory potency at α6β2-containing nicotinic receptors mediating nicotine-evoked dopamine release. Biochemical Pharmacology, 80(3), 402-409. https://doi.org/10.1016/j.bcp.2010.03.018

@article{4d9bf34e97414a5dad7e69107c02c79c,

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

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.",

keywords = "Dopamine release, Nicotine, Nicotinic acetylcholine receptor, Nicotinic receptor antagonist, Smoking cessation",

author = "Smith, \{Andrew M.\} and Marharyta Pivavarchyk and Wooters, \{Thomas E.\} and Zhenfa Zhang and Guangrong Zheng and McIntosh, \{J. Michael\} and Crooks, \{Peter A.\} and Bardo, \{Michael T.\} and Dwoskin, \{Linda P.\}",

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. ",

year = "2010",

month = aug,

doi = "10.1016/j.bcp.2010.03.018",

language = "English",

volume = "80",

pages = "402--409",

number = "3",

}

Smith, AM, Pivavarchyk, M, Wooters, TE, Zhang, Z, Zheng, G, McIntosh, JM, Crooks, PA, Bardo, MT & Dwoskin, LP 2010, 'Repeated nicotine administration robustly increases bPiDDB inhibitory potency at α6β2-containing nicotinic receptors mediating nicotine-evoked dopamine release', Biochemical Pharmacology, vol. 80, no. 3, pp. 402-409. https://doi.org/10.1016/j.bcp.2010.03.018

TY - JOUR

T1 - Repeated nicotine administration robustly increases bPiDDB inhibitory potency at α6β2-containing nicotinic receptors mediating nicotine-evoked dopamine release

AU - Smith, Andrew M.

AU - Pivavarchyk, Marharyta

AU - Wooters, Thomas E.

AU - Zhang, Zhenfa

AU - Zheng, Guangrong

AU - McIntosh, J. Michael

AU - Crooks, Peter A.

AU - Bardo, Michael T.

AU - Dwoskin, Linda P.

N1 - 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.

PY - 2010/8

Y1 - 2010/8

N2 - 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.

AB - 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.

KW - Dopamine release

KW - Nicotine

KW - Nicotinic acetylcholine receptor

KW - Nicotinic receptor antagonist

KW - Smoking cessation

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SN - 0006-2952

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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