Amphetamine enantiomers inhibit homomeric α7 nicotinic receptor through a competitive mechanism and within the intoxication levels in humans
| Autor: | Rafael Maldonado-Hernández, Daniel R. Garton, Matthias Quick, José E. Lizardi-Ortiz, Sharmaine G. Ross, José A. Lasalde-Dominicci |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
alpha7 Nicotinic Acetylcholine Receptor Motor Activity Pharmacology Binding Competitive Cholinergic Antagonists Article Xenopus laevis 03 medical and health sciences Cellular and Molecular Neuroscience Acetylcholine binding 0302 clinical medicine medicine Animals Humans Homomeric Amphetamine CA1 Region Hippocampal Cells Cultured Lymnaea Acetylcholine receptor Mice Knockout Neurons Binding Sites Dose-Response Relationship Drug Chemistry Antagonist Hydrogen Bonding Methamphetamine Mice Inbred C57BL Molecular Docking Simulation 030104 developmental biology Knockout mouse Oocytes Central Nervous System Stimulants 030217 neurology & neurosurgery Acetylcholine medicine.drug |
| Zdroj: | Neuropharmacology. 144:172-183 |
| ISSN: | 0028-3908 |
| DOI: | 10.1016/j.neuropharm.2018.10.032 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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