Hernandez-Abrego_2026_Neuropharmacol_283_110736

GABAergic synaptic transmission is modulated by nicotinic acetylcholine receptors (nAChRs) and both are regulated by several substances, including antidepressants and acetylcholinesterase inhibitors. They may therefore be involved in disorders such as depression. Physostigmine (an acetylcholinesterase inhibitor), besides inducing depressive behaviors, is an agonist and positive allosteric modulator of nAChRs; however, its effects on both GABAergic transmission and alpha7 nAChRs are not clear. Here we explore the pharmacological actions of physostigmine on both GABAergic transmission and alpha7 nAChRs in the hippocampus by using voltage-clamp technique. We found in rat hippocampal CA1 stratum radiatum interneurons that, a) physostigmine increased the frequency of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs), which was reversed by mecamylamine (a non-selective nAChR antagonist) and by methyllycaconitine (a selective alpha7 nAChR antagonist); but not by dihydro-beta-erythroidine (a selective alpha4beta2 nAChR antagonist), b) methyllycaconitine alone decreased the frequency of sIPSCs, c) the antidepressant fluoxetine decreased the frequency of sIPSCs that was potentiated by physostigmine, and had no effect after methyllycaconitine application, d) physostigmine potentiated the ionic current induced by choline without modifying its decay time constant, and was inhibited by fluoxetine. Finally, in hippocampal CA1 pyramidal neurons, physostigmine decreased the frequency of sIPSCs, which was reverted by fluoxetine. In conclusion, physostigmine increases GABAergic synaptic transmission in hippocampal CA1 stratum radiatum interneurons acting as a type I positive allosteric modulator on tonic endogenous activated alpha7 nAChRs. These effects of physostigmine might be counteracted by fluoxetine, through inhibition of alpha7 nAChRs.