Molecular Mechanism of Inhibition of Nicotinic Receptors by Tricyclic Antidepressants.

F. GUMILAR; C. BOUZAT

Buenos Aires, Argentina.

Congreso; XIV International Biophysics Congress; 2002

IUPAB - SAB.

The nicotinic receptor (AChR) is the paradigm of the ligand-gated ion channel (LGIC) superfamily. In addition to the inhibition of the reuptake of monoamines, several antidepressants have been found to inhibit LGICs. However, the molecular mechanism of this inhibition is not fully understood. Therefore, we analyzed in detail the action of tricyclic antidepressants (Amitriptiline, Imipramine, Doxepin) on the muscle AChR at both the single channel and macroscopic current levels. The main effect of all antidepressants is a profound concentration-dependent decrease in both the frequency of opening events and the duration of clusters (8-fold at 20 µM) of AChRs activated by high acetylcholine concentrations. Antidepressants also significantly increase the decay rate of macroscopic currents elicited by rapid perfusion of acetylcholine to outside-out patches. Thus, results from both single-channel and macroscopic current recordings indicate that tricyclic antidepressants increase the rate of AChR desensitization. According to this conclusion, in equilibrium agonist-binding assays, antidepressants promote the typical high-affinity desensitized state. The present results could be extrapolated to other subtypes of AChRs found in brain as well as to other receptors of the LGIC superfamily.