Receptor Agonist 1S Research Articles

Reduction of the Scopolamine-Induced Impairment of Passive-Avoidance Performance by σ Receptor Agonist in Mice

Senda, T., K. Matsuno, T. Kobayashi and S. Mita. Reduction of the scopolamine-induced impairment of passive-avoidance performance by σ receptor agonist in mice. Physiol Behav 61(2) 257–264, 1997.—We examined the ameliorating effects of several σ receptor agonists on scopolamine-induced memory impairment in mice. Scopolamine was administered IP 30 min before the training session. Each σ receptor agonist was administered 60 min before or immediately after the training session, or 60 min before the retention test in the passive-avoidance performance experiments. (+)-N-Allylnormetazocine ((+)-SKF-10,047), a prototype σ1 receptor agonist, showed an ameliorating effect on the scopolamine-induced memory impairment in these 3 administration schedules, and (−)-SKF-10,047, a stereoisomer with low affinity for the σ1 receptor subtype, failed to reduce this memory impairment in mice. In addition, 1,3-di(2-tolyl)guanidine (DTG) and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperizine ((+)-3-PPP), nonselective σ receptor agonists, did not affect this memory impairment. Physostigmine, an acetylcholinesterase (AChE) inhibitor, alleviated the scopolamine-induced memory impairment in all these drug administration schedules. In addition, (+)-SKF-10,047-induced antiamnesic effect was antagonized by the concurrent administration of haloperidol, a σ receptor antagonist, or N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride (NE-100), a selective σ1 receptor antagonist. These findings indicate that the σ1 receptor agonist has ameliorating effects on all phases of learning and memory processes. This profile of σ1 receptor agonist is similar to that of an AChE inhibitor.

Ameliorating effect of SA4503, a novel σ1 receptor agonist, on memory impairments induced by cholinergic dysfunction in rats

We found a potent and selective σ 1 receptor agonist, SA4503 (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride), with high affinity for the σ 1 receptor subtype (IC 50 = 17 nM), but low affinity for the σ 2 receptor subtype (IC 50 = 1800 nM). The binding activity and selectivity of SA4503 resembled those of (+)-pentazocine, a prototype σ 1 receptor agonist. We have previously shown that the σ 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 α-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-butanone (haloperidol), a σ receptor antagonist, and N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100), a putative σ 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 σ 1 receptor subtype.

P-19-33 - Beta-25–35 induces neurotoxicity by altering calcium homeostasis in cerebellar granule cells

Senda, T., K. Matsuno, T. Kobayashi and S. Mita. Reduction of the scopolamine-induced impairment of passive-avoidance performance by σ receptor agonist in mice. Physiol Behav 61(2) 257–264, 1997.—We examined the ameliorating effects of several σ receptor agonists on scopolamine-induced memory impairment in mice. Scopolamine was administered IP 30 min before the training session. Each σ receptor agonist was administered 60 min before or immediately after the training session, or 60 min before the retention test in the passive-avoidance performance experiments. (+)-N-Allylnormetazocine ((+)-SKF-10,047), a prototype σ1 receptor agonist, showed an ameliorating effect on the scopolamine-induced memory impairment in these 3 administration schedules, and (−)-SKF-10,047, a stereoisomer with low affinity for the σ1 receptor subtype, failed to reduce this memory impairment in mice. In addition, 1,3-di(2-tolyl)guanidine (DTG) and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperizine ((+)-3-PPP), nonselective σ receptor agonists, did not affect this memory impairment. Physostigmine, an acetylcholinesterase (AChE) inhibitor, alleviated the scopolamine-induced memory impairment in all these drug administration schedules. In addition, (+)-SKF-10,047-induced antiamnesic effect was antagonized by the concurrent administration of haloperidol, a σ receptor antagonist, or N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride (NE-100), a selective σ1 receptor antagonist. These findings indicate that the σ1 receptor agonist has ameliorating effects on all phases of learning and memory processes. This profile of σ1 receptor agonist is similar to that of an AChE inhibitor.

P-19-31 - Effect of “Kangenkaryu” on cerebral blood flow and gene expression in rat

We examined the effects of σ1 receptor agonists against glutamate-induced neurotoxicity in cultured retinal neurons. Primary cultures obtained from fetal rat retinas (16–19 d gestation) were used. The neurotoxic effect of glutamate was quantitatively assessed using the trypan blue exclusion method. A brief exposure of retinal cultures to glutamate (500 μM) led to delayed neuronal cell death. The glutamate-induced neurotoxicity was inhibited by (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,b]-cyclohepten-5,10-imine hydrogen maleate (MK-801). The σ1 receptor agonists, 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)-piperazine dihydrochloride (SA4503) and (+)-pentazocine at a concentration range of 0.1~100 μM reduced the glutamate-induced neurotoxicity in a dose-dependent manner. In addition, the neuroprotective effects of both SA4503 and (+)-pentazocine were antagonized by co-treatment with N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride (NE-100), a putative σ1 receptor antagonist. These findings suggest that σ1 receptor agonists protect retinal cells against glutamate-induced neurotoxicity.

Binding properties of SA4503, a novel and selective σ1 receptor agonist

The binding profiles of SA4503 (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride), a novel σ receptor ligand, to σ 1 and σ 2 receptor subtypes in guinea pig and rat brain membranes were evaluated. SA4503 showed a high affinity for the σ 1 receptor subtype labeled by (+)-[ 3H]pentazocine (IC 50 = 17.4 ± 1.9 nM), while it had about 100-fold less affinity for the σ 2 receptor subtype labeled by [ 3H]1,3-di(2-tolyl)guanidine ([ 3H]DTG) in the presence of 200 nM (+)-pentazocine. SA4503 showed little affinity for 36 other receptors, ion channels and second messenger systems. The inhibition curves of SA4503 for (+)-[ 3H]pentazocine binding were shifted to the right in the presence of guanosine 5′- o-(3-thiotriphosphate) (GTPγS), as similar to those of (+)-3-(3-hydroxyphenyl)- N-(1-propyl)piperidine ((+)-3-PPP) and (+)-pentazocine, σ 1 receptor agonists. SA4503 significantly increased the K D value, but did not affect the B max value for specific (+)-[ 3H]pentazocine binding. These results indicated that SA4503 is a potent and selective agonist for the σ 1 receptor subtype in the brain. In addition, SA4503 inhibited specific (+)-[ 3H]pentazocine binding in a competitive manner.

P-19-27 - Effect of dynorphin A (1–13) on decrease in acetylcholine release induced by carbachol in rats

The selective σ1 receptor agonist 1-(3,4-dimethoxyphenethyl)-4-(3-phenyl propyl)piperazine dihydrochloride (SA4503) was reported to reverse the amnesia induced by the muscarinic receptor antagonist scopolamine at sub-mg/kg doses. We examined its effect on the learning impairment induced in mice by the non-competitive NMDA receptor antagonist dizocilpine. Learning capacities were evaluated using spontaneous alternation in the Y-maze for spatial working memory, and step-down type passive avoidance. SA4503 (0.03–1 mg/kg s.c.) attenuated the dizocilpine (0.15 mg/kg i.p.)-induced memory deficits following a bell-shaped curve in both tests. These effects of SA4503 were blocked by haloperidol (0.05 mg/kg i.p.), implicating σ1 receptors. SA4503 also reversed the alternation deficit induced by Nω-nitro-l-arginine methyl ester (l-NAME, 100 mg/kg i.p.) at the same dosage, indicating that it acted on working memory through the nitric oxide (NO)-mediated signalling pathway. Furthermore, progesterone (2 mg/kg s.c.) blocked the SA4503 effects in the dizocilpine- and l-NAME-amnesia models, in accordance with the purported neurosteroids/σ1 receptors interaction. These results demonstrate a promising neurobehavioural profile of SA4503, a ligand equally efficient to reverse the deficit in the glutamatergic as well as in the cholinergic amnesia model. Pertinent informations on the potential mechanism of the anti-amnesic effects of σ1 receptor ligands were also obtained.