Involvement of the sigma 1 ( σ 1 ) receptor in the anti‐amnesic, but not antidepressant‐like, effects of the aminotetrahydrofuran derivative ANAVEX1‐41

Background and purpose: Tetrahydro‐N, N‐dimethyl‐5, 5‐diphenyl‐3‐furanmethanamine hydrochloride (ANAVEX1‐41) is a potent muscarinic and sigma 1 ( σ 1 ) receptor ligand. The σ 1 receptor modulates glutamatergic and cholinergic responses in the forebrain and selective agonists are potent anti‐amnesic and antidepressant drugs. We have here analysed the σ 1 component in the behavioural effects of ANAVEX1‐41. Experimental approach: Binding of ANAVEX1‐41 to muscarinic and σ 1 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 (M 1 >M 3 , M 4 >M 2 with K i ranging from 18 to 114 nM) and selective σ 1 ligand ( σ 1 , K i =44 nM; σ 2 , K i =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 σ 1 antagonist BD1047 blocked the anti‐amnesic effect of ANAVEX1‐41 on both short‐ and long‐term memories. Pretreatment with a σ 1 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 σ 1 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 σ 1 receptors. The latter component may be involved in the enhancing effects of the drug on long‐term memory processes. British Journal of Pharmacology (2007) 152 , 267–279; doi: 10.1038/sj.bjp.0707386