Amphetamine enantiomers inhibit homomeric α7 nicotinic receptor through a competitive mechanism and within the intoxication levels in humans.

Autor: Garton DR; Columbia College of Columbia University, New York, NY, 10027, USA., Ross SG; Department of Biobehavioral Sciences, Teachers College Columbia University, New York, NY, 10027, USA., Maldonado-Hernández R; Department of Biology, University of Puerto Rico, Río Piedras Campus, San Juan, PR, 00931, USA., Quick M; Department of Psychiatry, Molecular Therapeutics Division, Columbia University Medical Center, New York, NY, 10032, USA., Lasalde-Dominicci JA; Departments of Biology and Chemistry, University of Puerto Rico, Río Piedras Campus, San Juan, PR, 00931, USA; Molecular Sciences Research Center, University of Puerto Rico, San Juan, PR, 00927, USA., Lizardi-Ortiz JE; Molecular Sciences Research Center, University of Puerto Rico, San Juan, PR, 00927, USA; Departments of Neurology and Psychiatry, Columbia University Medical Center, New York, NY, 10032, USA. Electronic address: jelizardiortiz@gmail.com.
Jazyk: angličtina
Zdroj: Neuropharmacology [Neuropharmacology] 2019 Jan; Vol. 144, pp. 172-183. Date of Electronic Publication: 2018 Oct 23.
DOI: 10.1016/j.neuropharm.2018.10.032
Abstrakt: Amphetamine-type stimulants (ATS) are the second most consumed illicit drug worldwide and lack good treatments for associated substance use disorders, lagging behind other addictive drugs. For this reason, a deeper understanding of the pharmacodynamics of ATS is required. The present study seeks to determine amphetamine (AMPH) enantiomers' effects on the homomeric α7 nicotinic acetylcholine receptor (α7 nAChR). Here we have shown that AMPH enantiomers bind to the α7 nAChR and competitively inhibit acetylcholine responses. Our in silico docking analysis suggests that AMPH binds close to the β7 strand of the B-loop of a chimera comprising of the human α7 nAChR and the acetylcholine binding protein from Lymnaea stagnalis. This may inhibit the required movement of the C-loop for channel opening, due to steric hindrance, providing a structural mechanism for its antagonist effect. Finally, we have shown that, in α7 nAChR full knockout mice, the behavioral response to D-AMPH is attenuated, providing direct evidence for the role of α7 nAChRs on the physiological response to D-AMPH. Importantly, D-AMPH exerts these effects at concentrations predicted to be pharmacologically relevant for chronic methamphetamine users and during binges. In conclusion, our data present new findings that implicate the α7 nAChR on the pharmacodynamics of ATS, which may be important for behavioral responses to these drugs, indicating a potential role for α7 nAChRs in ATS substance-use disorders.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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