Neuroscience Letters 607 (2015) 35–39 Contents lists available at ScienceDirect Neuroscience Letters jo ur nal ho me page: www.elsevier.com/locate/neulet Research paper Dual effects of a 2-benzylquinuclidinium derivative on 7-containing nicotinic acetylcholine receptors in rat hippocampal interneurons Jhon J. López a , Edwin G. Pérez a,∗ , Jesús García-Colunga b,∗∗ a Department of Organic Chemistry, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Av. Vicu˜ na Mackenna 4860, Casilla 306, Correo 22, Santiago, Chile b Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Campus Juriquilla, Boulevard Juriquilla 3001, Querétaro 76230, Mexico h i g h l i g h t s • 8d has high and low inhibitory affinities for 7 nAChRs in hippocampal interneurons. • 8d exerts an early potentiation and a late inhibition of the Ch-induced current. • The two opposite actions of 8d depends on the membrane potential. • 8d molecule interacts with at least two sites into the ion channel/receptor complex. • 8d is an antagonist and positive modulator of 7 nAChRs in hippocampal interneurons. a r t i c l e i n f o Article history: Received 9 June 2015 Received in revised form 9 September 2015 Accepted 14 September 2015 Available online 15 September 2015 Keywords: 7 Alpha Nicotinic acetylcholine receptor Dual modulation Hippocampus 2-Benzylquinuclidine derivatives a b s t r a c t Nicotinic acetylcholine receptors (nAChRs) are widely distributed in the brain. Particularly 7-containing nAChRs, associated with several physiological roles and pathologies, are one of the most abundant. Here, we studied 2-(4-hexyloxybenzyl)-1-methylquinuclidin-1-ium iodide (designated as 8d), on ion currents elicited by choline, I Ch , (Ch, a selective agonist for 7-containing nAChRs), recorded in interneurons from the stratum radiatum of the rat hippocampal CA1 region by using the whole-cell voltage-clamp technique. The 8d-concentration/Ch-response relationship exhibited high and low inhibitory affinities for 7-containing nAChRs, with IC 50 values of 0.59 and 6.80 M, respectively. Interestingly, 8d in a range of 3–10 M exerted opposite effects: a short early potentiation and a long late inhibition of the I Ch ; and 8d alone elicited a non-decaying inward current. Furthermore, potentiation and inhibition of the I Ch by 8d depended on the membrane potential, both being stronger at -20 than at -70 mV; indicating that 8d interacts with at least two sites into the ion channel/receptor complex: one for potentiating and another for inhibiting the 7-containing nAChRs. These results suggest that 8d may act as agonist, antagonist and positive modulator of 7-containing nAChRs in hippocampal interneurons. © 2015 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Nicotinic acetylcholine receptors (nAChRs) are ligand-gated cation channels belonging to the Cys-loop receptor superfamily. They are pentameric proteins made up of combinations of dis- tinct subunits (2–10 and 2–4) with two binding sites for ACh, or homomeric 7, 8 or 9 nAChRs with five identical binding ∗ Corresponding author. Fax: +52 442 238 1063. ∗∗ Corresponding author. E-mail addresses: eperezh@uc.cl (E.G. Pérez), garciacolunga@unam.mx (J. García-Colunga). sites [1,2]. Moreover, the 72 combination also forms functional nAChRs [3]. Both 42 and 7 nAChRs are the most abundant subtypes in brain regions [2,4]. For instance, 7 nAChRs are present in the hip- pocampus, thalamus, prefrontal cortex, subcortical basal ganglia, dopaminergic neurons in the ventral midbrain, and raphe seroto- nergic neurons [2,5]. The function and malfunction of nAChRs are associated with several physiological responses and brain disorders: brain development, learning, cognition, memory, Alzheimer’s disease, schizophrenia, epilepsy, depressive disorders, and drug addiction [2,4–7]. For this reason, nAChRs are considered as therapeutic targets for several diseases. Selective nicotinic ligands (agonists, http://dx.doi.org/10.1016/j.neulet.2015.09.016 0304-3940/© 2015 Elsevier Ireland Ltd. All rights reserved.