Functional and structural interactions between selective serotonin reuptake inhibitors and nicotinic acetylcholine receptors

Abstract

Neuronal nicotinic acetylcholine receptors (nAChRs) are involved in the regulation of mood and their related disorders such as anxiety and major depressive disorder. For example, there is a clear and strong association between major depression and smoking, where depressed patients smoke twice more than the non-depressed population, and opposite to that, nicotine consumption may lead to depressive symptoms. In patients with major depressive disorder, although the number of nAChRs is not altered, there is a low availability of nAChRs, possibly caused by higher endogenous ACh levels and the consequent nAChR desensitization, consistent with the cholinergic hypothesis of depression, in which the cholinergic systems is hypersensitive. Moreover, studies using animal models of depression reveal that nicotine-evoked serotonin release is mediated by nAChR activation compensating the deficiency of serotonin in depressed conditions. It was also reported that several common clinically prescribed antidepressants, including selective serotonin reuptake inhibitors (SSRIs), inhibit different nAChRs by non-competitive mechanisms, including ion channel blockade and accelerating nAChR desensitization. More specifically, SSRIs decrease channel open time without changing the single-channel conductance, indicating that these antidepressants act as open-channel blockers. Furthermore, inactive doses of citalopram, a SSRI antidepressant, and of PNU-28298, an α7 nAChR agonist, exert antidepressant-like effects. According with functional and structural results, SSRIs (e.g., fluoxetine) and tricyclic antidepressants (e.g., imipramine) bind to overlapping sites located within the nAChR ion channel in the desensitized and resting states.