1-(3-4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine-dihydrochloride and Learning-Disabilities

The sigma1 (sigma1) receptor cDNA was recently cloned in several animal species, including the mouse. In order to firmly establish the implication of sigma1 receptors in memory, a phosphorothioate-modified antisense oligodeoxynucleotide (aODN) targeting the sigma1 receptor mRNA and a mismatched analog (mODN) were administered intracerebroventricularly for 3 days in mice. Scatchard analyses of in vitro (+)-[3H]SKF-10,047 binding to sigma1 sites showed that Bmax values were significantly decreased in the hippocampus (-58.5%) and cortex (-38.1%), but not in the cerebellum, of aODN treated mice, as compared to saline- or mODN-treated animals. In vivo binding levels were also significantly decreased after aODN treatment in the hippocampus and cortex but not in the cerebellum. The anti-amnesic effects of the selective sigma1 agonists PRE-084 or SA4503 were evaluated against the learning impairments induced by dizocilpine or scopolamine, respectively, using spontaneous alternation behavior and passive avoidance task. The anti-amnesic effects of PRE-084 or SA4503, observed after saline- or mODN-treatment, were blocked after aODN administration. These observations bring a molecular basis to the modulatory role of sigma1 receptors in memory processes.

Topics: Amnesia; Animals; Brain; Dizocilpine Maleate; Excitatory Amino Acid Agonists; In Vitro Techniques; Learning Disabilities; Male; Maze Learning; Mice; Morpholines; Nootropic Agents; Oligonucleotides, Antisense; Phenazocine; Piperazines; Receptors, sigma

We investigated the effect of successive administrations of SA4503 (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride), a novel cognitive enhancer with high affinity and selectivity for the sigma1 receptor subtype, on the cortical cholinergic dysfunction-induced impairment of the spatial learning performance in the Morris water maze (MWM) task in rats. The impairment of the spatial learning performance was produced by the ibotenic acid-induced lesion of the basal forebrain (BF) area in rats. Escape latencies to find the platform during the training trials of the MWM task were significantly prolonged in the BF-lesioned rats compared with the sham-operated rats. Daily treatment with SA4503 (0.1-0.5 mg/kg, P.O./day) for 13 days ameliorated this learning deficit. In the probe trial, BF-lesioned rats reduced the number of times each rat crossed the former platform location during the training trials (goal area) in comparison with sham-operated rats. Successive administrations of SA4503 (0.25 mg/kg, P.O./day) also significantly increased the BF lesion-induced reduction of the number of times each rat crossed the goal area. These results suggest that the successive administrations of SA4503 attenuate the impairment of the spatial learning performance in rats with cortical cholinergic dysfunction, and that SA4503 is useful as a therapeutic drug for Alzheimer's disease.

Topics: Animals; Corpus Striatum; Hippocampus; Learning Disabilities; Male; Maze Learning; Nootropic Agents; Piperazines; Prosencephalon; Psychomotor Performance; Rats; Rats, Inbred F344; Receptors, sigma