Anti‐amnesic effect of dimemorfan in mice

Dimemorfan, an antitussive for more than 25 years, has previously been reported to be a relative high-affinity ligand at sigma-1 (σ1) receptor with the Ki value of 151 nM. To test whether dimemorfan has anti-amnesic effects similar to a σ1 receptor agonist, this study examined its effects on scopolamine- and β-amyloid peptide-(25-35)-induced amnesia in mice. Dimemorfan (10–40 mg kg−1, i.p.) administered 30 min before the training trial, immediately after the training trial, or 30 min before the retention test significantly improved scopolamine (1 mg kg−1, i.p.)- or β-amyloid peptide-(25-35) (3 nmol mouse−1, i.c.v.)-induced amnesia in a step-through passive avoidance test. Dimemorfan (5–40 mg kg−1, i.p.) pretreatment also attenuated scopolamine (8 mg kg−1, i.p.)-induced amnesia in a water-maze test. And, these anti-amnesic effects of dimemorfan, like the putative σ1 receptor agonist (+)-N-allylnormetazocine ((+)-SKF-10047), were antagonized by a σ receptor antagonist haloperidol (0.25 mg kg−1, i.p.). These results indicated that dimemorfan has anti-amnesic effects and acts like a σ1 receptor agonist. Keywords: Dimemorfan, anti-amnesic effect, σ1 receptor, scopolamine, β-amyloid peptide-(25-35), step-through passive avoidance, water maze, (+)-SKF-10047, haloperidol Introduction Dimemorfan (d-3-methyl-N-methylmorphinan) is an analogue of dextromethorphan and both compounds are non-opioid antitussive drugs safely used in the clinic for more than 25 years (Kase et al., 1976). In addition, dextromethorphan has been shown to have anticonvulsant and neuroprotective effects in a variety of experimental models (Tortella & Musacchio, 1986; Choi, 1987; Leander et al., 1988; Steinberg et al., 1993). Our previous study demonstrated that dimemorfan has equipotent anticonvulsant effect as dextromethorphan, but does not produce phencyclidine-like hyperlocomotion exhibited by dextromethorphan in mice (Chou et al., 1999). Furthermore, we demonstrated that dimemorfan has a relative high affinity at sigma-1 (σ1) receptors (Ki=151 nM) vs sigma-2 receptors (Ki=4421 nM) as determined by receptor binding assay on rat brain membranes (Chou et al., 1999). The σ1 receptors are a subtype of σ receptors known to be widely distributed in the nervous, peripheral, endocrine, and immune systems (Su, 1991; Hanner et al., 1996). Over seven diverse structural classes of pharmacological agents, including morphinans (e.g., dextromethorphan), (+)-benzomorphans (e.g., (+)-N-allylnormetazocine ((+)-SKF-10047)), butyrophenones (e.g., haloperidol) and neurosteroids, can bind σ1 receptors with high affinity. The σ1 receptor has been cloned and its deduced amino acid sequence is 30% identical and 66% similar to a yeast C8-C7 sterol isomerase, but without similar enzymatic activity (Hanner et al., 1996; Prasad et al., 1998). σ1 receptors are ordinarily present in the endoplasmic reticulum, while in the presence of σ1 receptor ligand a part of σ1 receptors translocate to the nuclear membrane and plasma membrane (Morin-Surun et al., 1999; Hayashi et al., 2000). Despite the fact that it is not a GTP-binding protein coupled receptor, some effects at the σ1 receptor are indirectly inhibited by pertussis toxin (Monnet et al., 1994; Hayashi et al., 2000) and activation of this receptor can result in the recruitment of the subsequent, calcium-dependent phospholipase C and protein kinase C cascade (Morin-Surun et al., 1999). Hayashi & Su (2001) reported that σ1 receptor formed a trimeric complex with ankyrin B (a cytoskeletal adaptor protein) and inositol 1,4,5-trisphosphate (IP3) receptor and σ1 receptor agonists might modulate vesicle transport and neurotransmitter release by regulating the dynamics of ankyrin B. Although the precise physiological function of this receptor is unclear, many preclinical studies have implied that selective σ1 receptor ligands have therapeutic potentials in the treatment of certain disorders of central nervous system including learning and memory impairments (Maurice & Lockhart, 1997; Maurice et al., 1999; 2001). It is well known that central cholinergic system plays an important role in the learning and memory processes (Smith, 1988). The σ1 receptors appear to play a potent neuromodulatory role on the cholinergic neurotransmission including the enhancement of stimulus-evoked acetylcholine (ACh) release in cerebral and hippocampal slices in vitro (Siniscalchi et al., 1987; Junien et al., 1991) and the increment of the extracellular ACh concentrations in the rat frontal cortex and hippocampus in vivo (Matsuno et al., 1992; 1993a; 1995). Furthermore, several selective σ1 receptor ligands have been reported to have anti-amnesic effects against cholinergic dysfunction-induced memory impairments in rodents, including those induced by muscarinic ACh receptor antagonist scopolamine (Earley et al., 1991; Matsuno et al., 1993b; 1997), nicotinic ACh receptor antagonist mecamylamine (Maurice et al., 1994), choline uptake blocker hemicholinium-3 (Matsuno et al., 1994), the toxic aggregated β-amyloid peptide-(25-35) (Maurice et al., 1998), and the lesions of the basal forebrain (Senda et al., 1996). Although dimemorfan is a relative high affinity ligand at σ1 receptors, its putative anti-amnesic effect and σ1 receptor agonist properties are unclear. Therefore, this study examined the effects of dimemorfan on scopolamine- and β-amyloid peptide-(25-35)-induced amnesia in mice using a step-through passive avoidance test or a water-maze test and compared with those of the selective σ1 ligand (+)-SKF-10047.