2--hydroxy-5-9-dimethyl-2-allyl-6-7-benzomorphan and Amnesia

Both traditional and novel sigma (sigma)-receptor agonists have been reported to possess anti-amnesic effects in rodents. In particular, the anti-amnesic effects induced by the novel sigma1-receptor agonists, such as (+)-pentazocine, SA4503 and PRE-084, were shown in beta amyloid-peptide-induced, basal forebrain (BF)-lesioned and carbon monoxide (CO)-induced amnesia models and senescence-accelerated mouse (SAM). In addition, these sigma1-receptor agonists have good profiles for the central acetylcholine and dopamine systems. Moreover, they also have neuroprotective and anti-depressive effects. These evidence suggested that the sigma1-receptor agonists may be promising compounds for the treatment of dementing disorders such as Alzheimer's disease, senile dementia and vascular dementia. However, the sigma-receptor family is still considered to be enigmatic molecular targets. More molecular cloning and biochemical studies on the sigma-receptor family are needed.

Topics: Acetylcholine; Amnesia; Animals; Disease Models, Animal; Dopamine; Ligands; Mice; Morpholines; Pentazocine; Phenazocine; Piperazines; Receptors, sigma; Sigma-1 Receptor

(1) Dimemorfan, an antitussive for more than 25 years, has previously been reported to be a relative high-affinity ligand at sigma-1 (sigma(1)) receptor with the K(i) value of 151 nM. (2) To test whether dimemorfan has anti-amnesic effects similar to a sigma(1) receptor agonist, this study examined its effects on scopolamine- and beta-amyloid peptide-(25-35)-induced amnesia in mice. (3) 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 beta-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 sigma(1) receptor agonist (+)-N-allylnormetazocine ((+)-SKF-10047), were antagonized by a sigma receptor antagonist haloperidol (0.25 mg kg(-1), i.p.). (4) These results indicated that dimemorfan has anti-amnesic effects and acts like a sigma(1) receptor agonist.

Topics: Amnesia; Amyloid beta-Peptides; Animals; Avoidance Learning; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred ICR; Morphinans; Peptide Fragments; Phenazocine; Receptors, sigma; Scopolamine

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

The specific sigma-receptor agonist (+)-SKF 10047 and antagonist BD 1047 were used to investigate whether this receptor was involved in passive-avoidance training in the day-old chick. We found 300 microM (+)-SKF 10047 to be amnesic when injected into the lobus parolfactorius 5 h after training (p < .01). Higher or lower concentrations of (+)-SKF 10047 did not disrupt memory formation. The amnesia produced by the efficacious dose of (+)-SKF 10047 was reversed by the specific antagonist, BD 1047. It is suggested that the sigma-receptor may exert its effect on passive-avoidance memory consolidation during the later stages of long-term memory formation by modulation of memory-related neurotransmission.

Topics: Amnesia; Animals; Animals, Newborn; Antipsychotic Agents; Avoidance Learning; Chickens; Ethylenediamines; Olfactory Bulb; Phenazocine; Receptors, sigma; Synaptic Transmission

1. The sigma(1) (sigma(1)) receptor cDNA was cloned in several animal species. Molecular tools are now available to identify its endogenous effectors, such as neuroactive steroids, and to establish its precise physiological role. In particular, the sigma(1) receptor is involved in memory processes, as observed in pharmacological and pathological rodent models of amnesia. 2. In order to establish the involvement of sigma(1) receptors in memory, a 16-mer oligodeoxynucleotide antisense to the sigma(1) receptor cDNA (aODN), and its mismatched control (mODN) were prepared and centrally administered into the mouse brain. The anti-amnesic effects induced by the selective sigma(1) agonist PRE-084 and the steroid dehydroepiandrosterone (DHEA) sulphate or pregnenolone sulphate were examined in ODN-treated animals. 3. The aODN treatment failed to affect the dissociation constant (K(d)) but significantly decreased the number of sigma(1) sites (B(max)) labelled with [(3)H]-(+)-SKF-10,047 in the hippocampus and cortex. In these structures, the in vivo binding levels were also diminished, according to the dose and number of injections, as compared with control animals injected with saline or mODN. 4. Cannulation and injections failed to affect the open-field behaviour of the animals. However, the anti-amnesic effects of PRE-084 and DHEA sulphate against the dizocilpine-induced impairments were blocked after aODN treatment in the short- and long-term memory tests. The anti-amnesic effects of pregnenolone sulphate remained unchanged. 5. These observations bring a molecular basis to the modulatory role of sigma(1) receptors in memory, and reveal that the anti-amnesic action of neuroactive steroids may not similarly involve an interaction with sigma(1) receptors.

Topics: Amnesia; Animals; Avoidance Learning; Behavior, Animal; Binding Sites; Blotting, Western; Brain; Cerebral Cortex; Dehydroepiandrosterone; Dizocilpine Maleate; Dose-Response Relationship, Drug; Hippocampus; In Vitro Techniques; Learning Disabilities; Male; Maze Learning; Memory; Mice; Morpholines; Oligonucleotides, Antisense; Phenazocine; Pregnenolone; Receptors, sigma; Sigma-1 Receptor

The effects of the stereoisomers of N-allylnormetazocine (SKF-10,047) on the hippocampal cholinergic functions were compared in rats. A putative sigma 1 receptor agonist, (+)-SKF-10,047, elicited an increase of hippocampal extracellular acetylcholine level and anti-amnesic effect against scopolamine-induced memory dysfunctions in rats. These phenomena were not produced by (-)-SKF-10,047, and were reversed by haloperidol, a putative sigma 1 receptor antagonist. Such stereoselectivity and antagonism imply an involvement of sigma 1 receptors in these (+)-SKF-10,047-stimulated hippocampal cholinergic functions.

Topics: Acetylcholine; Amnesia; Analysis of Variance; Animals; Haloperidol; Hippocampus; Male; Muscarinic Antagonists; Phenazocine; Rats; Rats, Wistar; Receptors, sigma; Scopolamine; Stereoisomerism; Stimulation, Chemical; Synaptic Transmission

Three sigma receptor ligands were examined for their ameliorating effects on p-chloroamphetamine-induced amnesia in mice. p-Chloroamphetamine was administered intraperitoneally 30 min before the training session of the passive avoidance response. Each sigma receptor ligand was administered 60 min before or immediately after the training session, or 60 min before the retention test. (+)-N-Allylnormetazocine ((+)-SKF-10,047), a prototype benzomorphan sigma receptor ligand, significantly reduced the p-chloroamphetamine-induced amnesia in these three administration schedules, as do acetylcholinesterase inhibitors. On the contrary, the significant anti-amnesic effects elicited by non-benzomorphan sigma receptor ligands, 1,3-di-(2-tolyl)guanidine (DTG) or (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperizine ((+)-3-PPP), were observed depending upon the timing of their administration. In addition, the ameliorating effect of (+)-SKF-10,047 against the p-chloroamphetamine-induced amnesia was superior to that of (-)-SKF-10,047. The (+)-SKF-10,047-induced anti-amnesic effect was significantly antagonized by the concurrent administration of either scopolamine, a muscarinic receptor antagonist, or hemicholinium-3, an inhibitor of the Na(+)-dependent high-affinity choline uptake site. These findings indicated that sigma receptor ligands had anti-amnesic effects against drug-induced memory impairment. In addition, the anti-amnesic effect of (+)-SKF-10,047 was superior to those of other sigma receptor ligands, and was mediated by both the sigma receptor and the central acetylcholinergic system.

Topics: Acetylcholine; Amnesia; Animals; Anticonvulsants; Avoidance Learning; Brain; Cholinesterase Inhibitors; Dopamine Agonists; Electroshock; Guanidines; Ligands; Male; Memory; Mice; Mice, Inbred Strains; p-Chloroamphetamine; Phenazocine; Piperidines; Receptors, sigma; Serotonin Antagonists

JO 1784 ((+)-N-Cyclopropyl-methyl-N-methyl-1,4-diphenyl-1-yl-but-3-en-1-ylami ne, hydrochloride), has been recently described as a selective ligand for the sigma receptor with an IC50 of 39 +/- 8 nM28. In the present study the effects of JO 1784 on experimental induced amnesia were investigated using one trial passive avoidance task in rats. Amnesia was produced by injecting scopolamine (1 mg/kg i.p.) 30 min before the second session (T2) on day 2 of the passive avoidance task. The anti-amnesic effect of JO 1784 was compared with other typical and atypical psychotropic drugs which interact at the sigma and or the phencyclidine site. JO 1784 was studied at 5 doses; 0.0625, 0.25, 1.0, 4.0 and 16.0 mg/kg i.p. ((+)-3-(3-hydroxyphenyl)-N-1-(propyl)piperidine ((+)-3-PPP). Rimcazole, (+)-N-allylnormetazocine ((+)-NANM), 1,3-di(2-tolyl) guanidine (DTG) were studied at 4 doses; 0.25, 1.0, 4.0 and 8.0 mg/kg i.p. All drugs were administered 60 min before the test (T2) on day 2 i.e. 30 min before scopolamine. Piracetam (1000 mg/kg p.o.) administered in the same test conditions was used as a reference compound in each experiment. Of the drugs investigated JO 1784 (0.25, 1.0, 4.0 and 16.0 mg/kg i.p.), (+)-3-PPP (0.25, 1.0 and 4.0 mg/kg i.p.), DTG (1.0, 4.0 and 8.0 mg/kg) and piracetam significantly reversed scopolamine induced amnesia on day 3 (T3). At the lower dose, JO 1784 (0.0625 mg/kg) failed to reverse the amnesic effects of scopolamine on day 3. These results suggest that JO 1784 the selective sigma ligand, may be beneficial in amnesic status.

Topics: Amnesia; Animals; Antipsychotic Agents; Avoidance Learning; Behavior, Animal; Carbazoles; Cinnamates; Cyclopropanes; Dopamine Agents; Dose-Response Relationship, Drug; Guanidines; Ligands; Male; Phenazocine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma; Scopolamine