Involvement of the sigma1 (σ1) receptor in the anti-amnesic, but not antidepressant-like, effects of the aminotetrahydrofuran derivative ANAVEX1-41

Abstract

Background and purpose: Tetrahydro-N, N-dimethyl-5, 5-diphenyl-3- furanmethanamine hydrochloride (ANAVEX1-41) is a potent muscarinic and sigma1 (σ1) receptor ligand. The σ1 receptor modulates glutamatergic and cholinergic responses in the forebrain and selective agonists are potent anti-amnesic and antidepressant drugs. We have here analysed the σ1 component in the behavioural effects of ANAVEX1-41. Experimental approach: Binding of ANAVEX1-41 to muscarinic and σ1 receptors were measured using cell membranes. Behavioural effects of ANAVEX1-41 were tested in mice using memory (spontaneous alternation, passive avoidance, water-maze) and antidepressant-like activity (forced swimming) procedures. Key results: In vitro, ANAVEX1-41 was a potent muscarinic (M1>M3, M4>M2 with K i ranging from 18 to 114 nM) and selective σ1 ligand (σ1, Ki=44 nM; σ2, Ki=4 μM). In mice, ANAVEX1-41 failed to affect learning when injected alone (0.03-1 mg kg-1), but attenuated scopolamine-induced amnesia with a bell-shaped dose response (maximum at 0.1 mg kg-1). The σ1 antagonist BD1047 blocked the anti-amnesic effect of ANAVEX1-41 on both short- and long-term memories. Pretreatment with a σ1 receptor-directed antisense oligodeoxynucleotide prevented effects of ANAVEX1-41 only in the passive avoidance procedure, measuring long-term memory. ANAVEX1-41 reduced behavioural despair at 30 and 60 mg kg -1, without involving the σ1 receptor, as it was not blocked by BD1047 or the antisense oligodeoxynucleotide. Conclusions and implications: ANAVEX1-41 is a potent anti-amnesic drug, acting through muscarinic and σ1 receptors. The latter component may be involved in the enhancing effects of the drug on long-term memory processes. © 2007 Nature Publishing Group All rights reserved.