Cocaine potently blocks neuronal α3β4 nicotinic acetylcholine receptors in SH-SY5Y cells

Ze gang Ma, Nan Jiang, Yuan bing Huang, Xiao kuang Ma, Jason Brek Eaton, Ming Gao, Yong chang Chang, Ronald J. Lukas, Paul Whiteaker, Janet Neisewander, Jie Wu

Research output: Contribution to journalArticle

Abstract

Cocaine is one of the most abused illicit drugs worldwide. It is well known that the dopamine (DA) transporter is its major target; but cocaine also acts on other targets including nicotinic acetylcholine receptors (nAChRs). In this study, we investigated the effects of cocaine on a special subtype of neuronal nAChR, α3β4-nAChR expressed in native SH-SY5Y cells. α3β4-nAChR-mediated currents were recorded using whole-cell recordings. Drugs were applied using a computer-controlled U-tube drug perfusion system. We showed that bath application of nicotine induced inward currents in a concentration-dependent manner with an EC50 value of 20 µM. Pre-treatment with cocaine concentration-dependently inhibited nicotine-induced current with an IC50 of 1.5 μM. Kinetic analysis showed that cocaine accelerated α3β4-nAChR desensitization, which caused a reduction of the amplitude of nicotine-induced currents. Co-application of nicotine and cocaine (1.5 μM) depressed the maximum response on the nicotine concentration-response curve without changing the EC50 value, suggesting a non-competitive mechanism. The cocaine-induced inhibition of nicotine response exhibited both voltage- and use-dependence, suggesting an open-channel blocking mechanism. Furthermore, intracellular application of GDP-βS (via recording electrode) did not affect cocaine-induced inhibition, suggesting that cocaine did not alter receptor internalization. Moreover, intracellular application of cocaine (30 µM) failed to alter the nicotine response. Finally, cocaine (1.5 μM) was unable to inhibit the nicotine-induced inward current in heterologous expressed α63β2β3-nAChRs and α4β2-nAChRs expressed in human SH-EP1 cells. Collectively, our results suggest that cocaine is a potent blocker for native α3β4-nAChRs expressed in SH-SY5Y cells.

Original languageEnglish (US)
JournalActa Pharmacologica Sinica
DOIs
StateAccepted/In press - Jan 1 2019

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Nicotinic Receptors
Cocaine
Nicotine
Dopamine Plasma Membrane Transport Proteins
Street Drugs
Patch-Clamp Techniques
Baths
Pharmaceutical Preparations
Inhibitory Concentration 50
Electrodes
Perfusion

Keywords

  • cocaine
  • nicotinic acetylcholine receptor
  • open-channel block
  • patch-clamp
  • SH-SY5Y cells

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Ma, Z. G., Jiang, N., Huang, Y. B., Ma, X. K., Brek Eaton, J., Gao, M., ... Wu, J. (Accepted/In press). Cocaine potently blocks neuronal α3β4 nicotinic acetylcholine receptors in SH-SY5Y cells. Acta Pharmacologica Sinica. https://doi.org/10.1038/s41401-019-0276-y

Cocaine potently blocks neuronal α3β4 nicotinic acetylcholine receptors in SH-SY5Y cells. / Ma, Ze gang; Jiang, Nan; Huang, Yuan bing; Ma, Xiao kuang; Brek Eaton, Jason; Gao, Ming; Chang, Yong chang; Lukas, Ronald J.; Whiteaker, Paul; Neisewander, Janet; Wu, Jie.

In: Acta Pharmacologica Sinica, 01.01.2019.

Research output: Contribution to journalArticle

Ma, Ze gang ; Jiang, Nan ; Huang, Yuan bing ; Ma, Xiao kuang ; Brek Eaton, Jason ; Gao, Ming ; Chang, Yong chang ; Lukas, Ronald J. ; Whiteaker, Paul ; Neisewander, Janet ; Wu, Jie. / Cocaine potently blocks neuronal α3β4 nicotinic acetylcholine receptors in SH-SY5Y cells. In: Acta Pharmacologica Sinica. 2019.
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AU - Brek Eaton, Jason

AU - Gao, Ming

AU - Chang, Yong chang

AU - Lukas, Ronald J.

AU - Whiteaker, Paul

AU - Neisewander, Janet

AU - Wu, Jie

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