(+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress through the activation of phenytoin-regulated σ1 sites

doi:10.1016/0014-2999(95)00830-6

European Journal of Pharmacology

Volume 299, Issues 1–3, 28 March 1996, Pages 21-28

https://doi.org/10.1016/0014-2999(95)00830-6 Get rights and content

Abstract

Mice exhibited a marked suppression of motility when they were replaced in the same environment in which they had previously received an electric footshock. This psychological stress-induced motor suppression, known as conditioned fear stress, was dose dependently attenuated by (+)-N-allylnormetazocine ((+)-SKF-10,047) and by dextromethorphan, putative σ receptor agonists, but not by other σ receptor ligands, (+)-pentazocine and 1,3-di-(2-tolyl)guanidine (DTG). Unlike (+)-SKF-10,047 and dextromethorphan, the non-competitive NMDA receptor antagonists, phencyclidine and dizocilpine, attenuated the conditioned fear stress only at high doses that induced marked hypermotility in non-stressed mice. The effects of (+)-SKF-10,047 and dextromethorphan, but not phencyclidine and dizocilpine, on the conditioned fear stress were antagonized by the σ receptor antagonists, NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ehylamine monohydrochloride) and BMY-14802 (α-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol hydrochloride). Interestingly, the effects of (+)-SKF-10,047 and dextromethorphan on the stress response were enhanced by combination with phenytoin, an anticonvulsant drug, whereas those of (+)-pentazocine, DTG, phencyclidine, and dizocilpine were not. These results suggest that activation of phenytoin-regulated type σ₁ receptors, but not of phencyclidine receptors, is involved in the ameliorating effects of (+)-SKF-10,047 and dextromethorphan on stress-induced motor suppression.

References (31)

D.L. DeHaven-Hudkins et al.
Allosteric modulation of ligand binding to [³H]-(+)pentazocine-defined σ recognition sites by phenytoin
Life Sci.
(1993)
A.L. Gundlach et al.
Phencyclidine and σ opiate receptors in brain: biochemical and autoradiographical differentiation
Eur. J. Pharmacol.
(1985)
S.B. Hellewell et al.
A sigma-like binding site in rat pheochromocytoma (PC12) cells: Decreased affinity for (+)-benzomorphans and lower molecular weight suggest a different sigma receptor form from that of guinea pig brain
Brain Res.
(1990)
H. Kamei et al.
SKF-10,047 reverses stress-induced motor suppression: interaction with dopaminergic system
Eur. J. Pharmacol.
(1994)
T. Kameyama et al.
The effect of analgesics on quickly learned conditioned suppression in mice
Neuropharmacology
(1982)
B.L. Largent et al.
Novel antipsychotic drugs share high affinity for σ receptors
Eur. J. Pharmacol.
(1988)
T.F. Murray et al.
Interaction of dextrorotatory opioids with phencyclidine recognition sites in rat brain membranes
Life Sci.
(1984)
T. Nabeshima et al.
Effect of opiate agonists on the conditioned suppression in motility of mice
Neurosci. Lett.
(1983)
R. Quirion et al.
Classification and nomenclature of phencyclidine and sigma receptor sites
Trends Pharmacol. Sci.
(1987)
R. Quirion et al.
A proposal for the classification of sigma binding sites
Trends Pharmacol. Sci.
(1992)

K Yamada et al.

Stress-induced behavioral responses and multiple opioid systems in the brain

Behav. Brain Res.

(1995)

B.R. Costa et al.

Synthesis and evaluation of optically pure [³H]-(+)-pentazocine, a highly potent and selective radioligand for σ receptors

FEBS Lett.

(1989)

M.S. Fanselow

Conditional and unconditional components of post-shock freezing

Pavlov J. Biol. Sci.

(1980)

A.L. Gundlach et al.

Autoradiographic localization of sigma receptor binding sites in guinea pig and rat central nervous system with (+)³H-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine

J. Neurosci.

(1986)

S.G. Holtzman

Discriminative stimulus effects of dextromethorphan in the rat

Psychopharmacology

(1994)

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In contrast to our expectations, DM had no statistically significant effect on pre-oligodendroglial cells subjected to hyperoxia. This might be attributable to different expression levels of the sigma-1 receptor, a known high-affinity DM target (Kamei et al., 1996), which shows lower expression levels in pre-oligodendrocytes than in immature oligodendrocytes (Hayashi and Su, 2004). This hypothesis is supported by a study by DeCoster and colleagues who found a correlation between sigma-1 site affinity and neuroprotective potency (DeCoster et al., 1995).
Preterm infants are prematurely subjected to relatively high oxygen concentrations, even when supplemental oxygen is not administered. There is increasing evidence to show that an excess of oxygen is toxic to the developing brain. Dextromethorphan (DM), a frequently used antitussive agent with pleiotropic mechanisms of action, has been shown to be neuroprotective in various models of central nervous system pathology. Due to its numerous beneficial properties, it might also be able to counteract detrimental effects of a neonatal oxygen insult. The aim of the current study was to evaluate its therapeutic potential in established cell culture and rodent models of hyperoxia-induced neonatal brain injury.
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DM significantly increased cell viability in immature oligodendroglial cells subjected to hyperoxia. In pre-oligodendroglial cells cell viability was not significantly affected by DM treatment. In vivo caspase-3 activation induced by hyperoxic exposure was significantly lower after administration of DM in gray and white matter areas. In control animals kept under normoxic conditions DM did not significantly influence caspase-3-dependent apoptosis. The present results indicate that DM is a promising and safe treatment strategy for neonatal hyperoxia-induced brain injury that merits further investigation.
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Selective agonists of the sigma-1 (σ₁) ligand–operated chaperone protein, like igmesine or PRE-084, are antidepressants in preclinical depression models. σ₁-Protein activation may contribute to the antidepressant efficacy of drugs known to act as selective serotonin-reuptake inhibitors (SSRI) or noradrenaline reuptake inhibitors through direct or indirect involvement of the σ₁-receptor in the drug effect. We here compared antidepressant effects in two behavioral procedures, the forced swimming test (FST) and conditioned fear stress (CFS). The involvement of the σ₁-receptor was examined using a co-treatment with the σ₁-antagonist BD1047 or using σ₁-knockout (KO) mice. Igmesine but not PRE-084 decreased FST immobility. The SSRI fluoxetine and sertraline, but not fluvoxamine, and the tricyclic antidepressants imipramine, desipramine, and amitriptyline were also effective. Only the effect of igmesine was blocked by BD1047 or in σ₁-KO mice. Igmesine, PRE-084, fluvoxamine, and sertraline decreased the CFS immobility in a BD1047- and σ₁-KO–sensitive manner. Among tricyclics, only amitriptyline was effective and its effect was unaffected by BD1047 or in σ₁-KO mice. The behavioral effects induced by mixed σ₁-receptor/SSRI antidepressants, like fluvoxamine or sertraline, may therefore involve a non-selective action at both targets. Moreover, the CFS appears to more reliably uncover a σ₁ pharmacological component in antidepressant screening.
Sigma-1 receptor knockout mice display a depressive-like phenotype
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Activation of sigma-1 receptors (Sig-1R) reportedly has antidepressant-like action. Limited data suggest that Sig-1Rs also modulate anxiety-related behaviors. The present experiments measured depressive-like, anxiety-like and motor behavior in Sig-1R knockout mice and their wildtype littermates. Sig-1R knockout mutants showed increased immobility in the forced swimming test, a depressive-like phenotype, but normal anxiety-like behavior in the elevated plus-maze and light/dark box tests and normal locomotor activity. The results further suggest that Sig-1Rs inversely modulate depressive-like behavior.
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2008, Journal of Pharmacological Sciences
We examined the effect of ramosetron, a potent serotonin (5-HT)₃-receptor antagonist for irritable bowel syndrome with diarrhea, on conditioned fear stress (CFS)-induced defecation and normal (non-stressed) defecation in rats and compared ramosetron with the antidiarrheal agent loperamide and the spasmolytic agents trimebutine and tiquizium. Ramosetron, loperamide, trimebutine, and tiquizium significantly inhibited CFS-induced defecation in a dose-dependent manner with ED₅₀(95% confidence limit) values of 0.019 (0.01 –0.028), 9.4 (4.0 –22), 850 (520 –2,400), and 300 (190 –450) mg/kg, respectively. A significant effect of ramosetron on CFS-induced defecation appeared at 10 min after dosing and was sustained for 8 h. In contrast, loperamide, trimebutine, and tiquizium significantly inhibited CFS-induced defecation between 1 –8, 1 –4, and 1–8h after administration, respectively. High doses of ramosetron did not affect normal defecation, whereas loperamide, trimebutine, and tiquizium significantly inhibited this process. In conclusion, ramosetron has potent, rapid-onset, and long-lasting inhibitory effects on CFS-induced defecation in rats, but does not influence normal defecation. The present findings indicate that ramosetron will be a useful therapeutic agent for irritable bowel syndrome with diarrhea, showing greater efficacy and safety than other antidiarrheal and spasmolytic agents.
Effect of ramosetron on conditioned emotional stress-induced colonic dysfunction as a model of irritable bowel syndrome in rats
2007, European Journal of Pharmacology
The aim of this study was to establish a pathophysiologic model of irritable bowel syndrome, and then to evaluate the pharmaceutical efficacy of ramosetron, a potent serotonin 3 (5-HT₃) receptor antagonist, and other anti-irritable bowel syndrome agents in this model. Rats stressed by a conditioned stress procedure exhibited marked prolongation of freezing time, an index of fear level, and an increase in the frequency of defecation (P < 0.01). A corticotropin-releasing factor (CRF) antagonist, α-helical CRF, inhibited both defecation and freezing behavior, while the antidiarrheal loperamide inhibited defecation only. The 5-HT₃ receptor antagonists ramosetron, cilansetron and alosetron also inhibited defecation (ED₅₀ values: 0.012, 0.094, 0.078 mg/kg p.o., respectively) without affecting freezing behavior. Ramosetron showed longer-lasting effect on defecation than cilansetron. Stress also resulted in increases in both proximal and distal colonic transit rates. Ramosetron and other 5-HT₃ receptor antagonists at doses inhibiting stress-induced defecation also ameliorated both stress-stimulated colonic transit rates. These results suggest that ramosetron, as well as agents used for the treatment of irritable bowel syndrome with diarrhea, has beneficial effects against emotional stress-induced colonic dysfunction. Furthermore, this emotional stress model may be useful in evaluation of drugs to treat irritable bowel syndrome presenting with diarrhea.
Involvement of the sigma<inf>1</inf> receptor in inhibiting activity of fluvoxamine on marble-burying behavior: Comparison with paroxetine
2007, European Journal of Pharmacology
In the present study, we examined the involvement of the sigma₁ receptor in the inhibitory effect of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine, compared with that of paroxetine, on marble-burying behavior, which is an animal model of obsessive–compulsive disorder. Sigma₁ receptor agonists (+)-SKF 10047 and PRE-084 significantly inhibited marble-burying behavior. Sigma receptor antagonist BD 1047 and selective sigma₁ receptor antagonist BD 1063 significantly attenuated the inhibition of marble-burying behavior by fluvoxamine. In contrast, selective sigma₂ receptor antagonist SM-21 failed to affect the inhibition of marble-burying behavior by fluvoxamine. On the other hand, BD 1047 and BD 1063 had no effect on the inhibition of marble-burying behavior by paroxetine. These observations show that activation of the sigma₁ receptor is a necessary component in the inhibitory effect of fluvoxamine on marble-burying behavior, and that the mechanism of its action is clearly different from that of paroxetine.

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(+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress through the activation of phenytoin-regulated σ1 sites

Abstract

Life Sci.

Eur. J. Pharmacol.

Brain Res.

Eur. J. Pharmacol.

Neuropharmacology

Eur. J. Pharmacol.

Life Sci.

Neurosci. Lett.

Trends Pharmacol. Sci.

Trends Pharmacol. Sci.

Behav. Brain Res.

Synthesis and evaluation of optically pure [3H]-(+)-pentazocine, a highly potent and selective radioligand for σ receptors

FEBS Lett.

Conditional and unconditional components of post-shock freezing

Pavlov J. Biol. Sci.

Autoradiographic localization of sigma receptor binding sites in guinea pig and rat central nervous system with (+)3H-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine

J. Neurosci.

Discriminative stimulus effects of dextromethorphan in the rat

Psychopharmacology

(+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress through the activation of phenytoin-regulated σ₁ sites

Synthesis and evaluation of optically pure [³H]-(+)-pentazocine, a highly potent and selective radioligand for σ receptors

Autoradiographic localization of sigma receptor binding sites in guinea pig and rat central nervous system with (+)³H-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine