Procognitive effects of varenicline in the animal model of schizophrenia depend on α4β2- and α7-nicotinic acetylcholine receptors

Abstract

Background: Varenicline, a partial agonist of the α4β2 nicotinic acetylcholine receptor (α4β2-nAChR), is currently used to facilitate smoking cessation. Preclinical and clinical studies have suggested that this compound may also be effective in treating cognitive impairments in schizophrenia. However, it is unclear which nicotinic acetylcholine receptor subtypes may be involved because varenicline is not only a partial agonist for α4β2-nAChRs but also a full agonist for α7 nicotinic acetylcholine receptors (α7-nAChRs). Aim: We investigated the effects of varenicline, compared to the α4β2-nAChR partial agonist TC-2403 and the α7-nAChR full agonist PNU-282987, in a ketamine-based model of schizophrenia-like cognitive deficits on the attentional set-shifting task in rats. The second goal was to elucidate whether the procognitive efficacy of varenicline was due to the compound’s action on α4β2-nAChRs or α7-nAChRs. Methods: Ketamine was administered to rats for 10 consecutive days and the test was performed 14 days following the last injection. The tested compounds were administered 30 min prior to the attentional set-shifting task. Results: Varenicline, TC-2403 and PNU-282987 ameliorated ketamine-evoked set-shifting deficits. While the α4β2-nAChR antagonist dihydro-β-erythroidine and the α7-nAChR antagonist methyllycaconitine completely prevented the procognitive actions of TC-2403 and PNU-282987, respectively, varenicline’s effect was only partially blocked by any given antagonist. Moreover, the combined treatment with TC-2403 and PNU-282987 more effectively facilitated rats’ set-shifting ability than activation of either type of nicotinic acetylcholine receptor alone. Conclusion: The present findings demonstrated that varenicline’s actions on both α7-nAChRs and α4β2-nAChRs may be necessary to produce its full procognitive effect in the present experimental setting.

A Pharmacological Comparison of Two Isomeric Nicotinic Receptor Agonists: The Marine Toxin Isoanatabine and the Tobacco Alkaloid Anatabine

“…It was recently reported that agonists that co-stimulate both of the major brain nAChRs have greater efficacy in protecting brain cells from β-amyloid [52]. Similarly, the precognitive effects of varenicline seem to depend on stimulation of both α4β2 and α7 nAChRs [53]. These interesting findings will stimulate further investigations of agonists that have this co-stimulatory ability at a common concentration.…”

Desformylflustrabromine, a positive allosteric modulator of α4β2-containing nicotinic acetylcholine receptors, enhances cognition in rats

“…dFBr and TC-2403 doses were based on our preliminary experiments (see Supplement 1) and previous studies demonstrating drug-evoked procognitive or behavioural effects [19,20,25,29]. Because the applied dose range was adjusted to demonstrate the minimal effective dose of the tested compounds, the dosage schedule differed between the ASST and NORT.…”

“…Because the applied dose range was adjusted to demonstrate the minimal effective dose of the tested compounds, the dosage schedule differed between the ASST and NORT. DHβE was administered at a dose that has been previously demonstrated to block the procognitive effects of TC-2403 [25,27]. The doses of ketamine and scopolamine, adopted from our published protocols [28,30], have been demonstrated to produce reliable impairment using the NORT.…”

In Vitro and In Vivo Models for the Investigation of Potential Drugs Against Schizophrenia

“…Administration of NMDA receptors antagonists (e.g., ketamine) induces a broad range of SZ-like impairments, including psychotic-like behaviors as well as negative symptoms and cognitive deficits. More specifically, administration of ketamine for 10 consecutive days produces distinct deficits in the ASST that may be attenuated by antipsychotic drugs [105] and nicotinic receptors ligands as well [104]. It was also demonstrated that selective impairments are found in the EDS phase after subchronic treatment with PCP (for seven days followed by seven days washout period).…”

“…This test requires animals to initially learn a rule and form an attentional 'set' within the same stimulus dimensions. In one ED phase of the ASST test, regarded as the index of cognitive flexibility, the rodent must switch their attention to a new, previously irrelevant stimulus dimension and discriminate between the odors and no longer between the media covering the bait [104]. Rats must perform a series of seven discriminations, including simple discrimination (SD), compound discrimination (CD), reversal 1 (R1), intra-dimensional shift (IDS), reversal 2 (R2), extra-dimensional shift (EDS), and reversal 3 (R3).…”