Interaction of nicotinic receptors with bupropion: Structural, functional, and pre-clinical perspectives

Abstract

Besides the antidepressant activity of bupropion (BP), preclinical studies in rodents provide evidence that this compound and its hydroxyl metabolites can attenuate nicotine withdrawal, reversing both the physical and negative affective aspects of nicotine abstinence. Co-interactions of BP with nicotine or other psychostimulants influence decrease anxiety- and cognitive- related processes. BP also attenuates the reinstatement of nicotine-induced conditioned place preference in rats caused by a priming dose of nicotine, morphine, cannabinoids, or ethanol. Therefore, BP can offer an interesting approach to the prevention of relapse in humans. There is emerging evidence that BP inhibits, in the low to intermediate micromolar range, various nicotinic acetylcholine receptors (AChRs) expressed in different neuronal pathways. The BP selectivity for different AChRs follows the sequence: ?3- > ?4- ~ ?1- > ?7-containing AChRs. This receptor blockade may contribute to its dual therapeutic activity as either an antidepressant or anti-nicotinic drug. Regarding the structural aspects, two distinct binding sites for [125I]SADU-3-72, a photosensitive derivative of BP, were identified in the Torpedo AChR. A binding site is located within the ion channel, which coincides with the molecular docking results, whereas a second site is found near the extracellular end of ?1-M1 when the receptor is in the desensitized state. Interestingly, BP greatly reduces the potentiating action elicited by Zn2+ on different non-?7 AChRs, and vice versa this cation increases the inhibitory strength of BP. This contrasting behavior supports the concept that the binding sites for BP and Zn2+are located at different domains. The understanding of the BP activity, alone or in combination with other drugs (e.g., nicotine), at the molecular and behavioral levels, may improve the knowledge of the underlying mechanisms of action. This knowledge is essential for the development of novel BP (or other antidepressant) derivatives with improved clinical profiles for the treatment of depression and psychostimulant-related addictions.