Bupropion, phencyclidine, and ibogaine each block two types of human nicotinic acetylcholine receptors (nAChR): the muscle-type (alpha1 beta gamma delta) and the ganglionic type (alpha3 beta4 alpha5+/-beta2). The blockade occurs at low to intermediate micromolar concentrations and cannot be overcome by increasing the amount of agonist, indicating noncompetitive inhibition. These findings suggest that nAChR are targets for diverse substances of abuse and for agents used in antiaddiction and smoking cessation strategies, and that nAChR may play underappreciated roles in depression and as targets for clinically useful antidepressants.
Psilocybin, a psychedelic tryptamine, shows promise for treating conditions like treatment-resistant depression and PTSD by rapidly improving depression scores. Its primary mechanism involves activating the serotonin 2A receptor, but downstream therapeutic effects remain unclear. This study analyzed dose- and sex-dependent transcriptional changes in mouse forebrains at 8 hours, 24 hours, and 7 days after a single low (0.25 mg/kg) or high (1 mg/kg) dose. Females showed faster transcriptional changes and attenuation at low doses compared to males, and more robust responses to high doses at early timepoints. Low-dose effects persisted at 7 days, outlasting high-dose changes, and involved pathways related to neuronal differentiation and neurogenesis. These sexually divergent and temporal molecular effects should inform treatment strategies and timing with cognitive behavioral therapy.