1-(3-4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine-dihydrochloride and Memory-Disorders

Rapid eye movement (REM) sleep deprivation (SD) decreases cerebral sigma-1 receptor expression and causes cognitive deficits. Sigma-1 agonists are cognitive enhancers. Here, we investigate the effect of cutamesine treatment in the REM SD model.. Sigma-1 receptor occupancy (RO) in the rat brain by cutamesine was determined using 1-[2-(3,4-dimethoxyphenethyl)]-4-(3-phenylpropyl)piperazine ([(11)C]SA4503) and positron emission tomography (PET), and tissue cutamesine levels were measured by ultra performance liquid chromatography (UPLC)-MS. RO was calculated from a Cunningham-Lassen plot, based on the total distribution volume of [(11)C]SA4503 determined by Logan graphical analysis. Cognitive performance was assessed using the passive avoidance (PA) test.. Cutamesine at a dose of 1.0 mg/kg reversed REM SD-induced cognitive deficit and occupied 92 % of the sigma-1 receptor population. A lower dose (0.3 mg/kg) occupied 88 % of the receptors but did not significantly improve cognition.. The anti-amnesic effect of cutamesine in this animal model may be related to longer exposure at a higher dose and/or drug binding to secondary targets.

Topics: Animals; Brain; Chromatography, High Pressure Liquid; Citalopram; Cognition; Male; Mass Spectrometry; Memory Disorders; Piperazines; Positron-Emission Tomography; Protein Binding; Rats; Rats, Wistar; Receptors, sigma; Sigma-1 Receptor; Sleep Deprivation; Sleep, REM

This study examined the effects of the sigma receptor ligands (+)-N-allylnormetazocine ((+)-SKF10,047) and 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) on dizocilpine-induced impairment of working and reference memory in a radial arm maze task in rats. Dizocilpine, a non-competitive NMDA receptor antagonist, significantly impaired both reference and working memory, an effect which was accompanied by ataxia and impairment of food intake. The dizocilpine-induced impairment of reference memory was dose-dependently attenuated by (+)-SKF10,047 and SA4503. SA4503 also attenuated the dizocilpine-induced working memory impairment, although (+)-SKF10,047 had no effect. Neither sigma receptor ligand affected the behavioral symptoms such as ataxia and impairment of food intake induced by dizocilpine. The ameliorating effects of both (+)-SKF10,047 and SA4503 on dizocilpine-induced spatial memory impairment were completely antagonized by a sigma1 receptor antagonist N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine-mon ohydrochloride. These results suggest that the interaction of sigma1 receptors with NMDA receptors modulates spatial memory in rats.

Topics: Animals; Ataxia; Dizocilpine Maleate; Dose-Response Relationship, Drug; Eating; Excitatory Amino Acid Antagonists; Male; Maze Learning; Memory Disorders; Nootropic Agents; Phenazocine; Piperazines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Receptors, sigma

We found a potent and selective sigma 1 receptor agonist, SA4503 (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydro-chloride), with high affinity for the sigma 1 receptor subtype (IC50 = 17 nM), but low affinity for the sigma 2 receptor subtype (IC50 = 1800 nM). The binding activity and selectivity of SA4503 resembled those of (+)-pentazocine, a prototype sigma 1 receptor agonist. We have previously shown that the sigma 1 receptor agonist activated central cholinergic functions. Therefore, we examined the effects of SA4503 on the cholinergic dysfunction-induced memory impairments in a passive avoidance task. Scopolamine, a muscarinic acetylcholine receptor antagonist, produced memory impairment, when it was administered 30 min before the training session of the passive avoidance task in rats. Single administration of SA4503 significantly reduced the scopolamine-induced memory impairment. In addition, the lesioning by injection of alpha-amino-3-hydroxy-5-isoxazole acetic acid (ibotenic acid) into the basal forebrain area produced memory impairment in rats. Repeated administration of SA4503 after lesioning of the basal forebrain area ameliorated the basal forebrain lesion-induced memory impairment. Moreover, the ameliorating effect of SA4503 against the scopolamine-induced memory impairment was antagonized by both 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-buta none (haloperidol), a sigma receptor antagonist, and N,N-dipropyl-2- [4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100), a putative sigma 1 receptor antagonist. These results suggest that SA4503 has an anti-amnesic effect against cholinergic dysfunction-induced memory impairment, and that the effect of SA4503 is mediated by the sigma 1 receptor subtype.

Topics: Animals; Avoidance Learning; Guinea Pigs; Ibotenic Acid; Male; Memory; Memory Disorders; Nootropic Agents; Pain Measurement; Pentazocine; Piperazines; Prosencephalon; Rats; Rats, Inbred F344; Rats, Wistar; Receptors, sigma; Scopolamine; Tacrine