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

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 alpha 7 nicotinic acetylcholine receptor (alpha 7 nAChR). Here we have shown that AMPH enantiomers bind to the alpha 7 nAChR and competitively inhibit acetylcholine responses. Our in silico docking analysis suggests that AMPH binds close to the beta 7 strand of the B-loop of a chimera comprising of the human alpha 7 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 alpha 7 nAChR full knockout mice, the behavioral response to D-AMPH is attenuated, providing direct evidence for the role of alpha 7 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 alpha 7 nAChR on the pharmacodynamics of ATS, which may be important for behavioral responses to these drugs, indicating a potential role for alpha 7 nAChRs in ATS substance-use disorders.