N-acetyl-L-cysteine inhibits marble-burying behavior in mice

In the present study, we examined the effect of N-acetyl-L-cysteine (NAC), a glutamate-modulating agent, on marble-burying behavior in mice. Fluvoxamine (30 mg/kg, p.o.) and mirtazapine (3 mg/kg, i.p.) significantly inhibited marble-burying behavior without affecting locomotor activity. Similarity, NAC (150 mg/kg, i.p.) significantly inhibited marble-burying behavior without affecting locomotor activity. On the other hand, the antioxidant α-tocopherol (10, 30, and 100 mg/kg, p.o.) had no effect on the marble-burying behavior. These results suggest that the glutamatergic system is involved in the marble-burying behavior, and NAC may be useful for treatment of OCD.     

Calcium-channel antagonists inhibit marble-burying behavior in mice

In the present study, we examined the effects of calcium-channel antagonists on marble-burying behavior, which is an animal model of obsessive-compulsive disorder. Amlodipine (10 mg/kg, i.p.), cilnidipine (10 mg/kg, i.p.), nilvadipine (3 and 10 mg/kg, i.p.), and flunarizine (30 mg/kg, i.p.) significantly inhibited marble-burying behavior in mice. These results suggest that calcium channels may be involved in the marble-burying behavior.     

Perospirone, a novel antipsychotic drug, inhibits marble-burying behavior via 5-HT1A receptor in mice: implications for obsessive-compulsive disorder

Perospirone is a novel atypical antipsychotic drug with dopamine (DA) D(2)- and serotonin (5-hydroxytryptamine, 5-HT) 5-HT(2A)-receptor antagonist, and 5-HT(1A)-receptor agonist properties. In the present study, we examined the effect of perospirone on marble-burying behavior, which has been considered an animal model of obsessive-compulsive disorder (OCD), compared with the effects of other antipsychotics such as haloperidol and risperidone. Perospirone at a dose of 10 mg/kg (p.o.) inhibited marble-burying behavior without affecting the locomotor activity in mice. On the other hand, haloperidol (0.1 mg/kg, i.p.) and risperidone (1 mg/kg, p.o.) showed significant suppression of locomotor activity at the dose that inhibited marble-burying behavior. Furthermore, the inhibition of marble-burying behavior by perospirone was antagonized by WAY100135 (10 mg/kg, i.p.), a selective 5-HT(1A)-receptor antagonist. WAY100135 at the same dose also antagonized the inhibition of marble-burying behavior by 8-OH-DPAT (3 mg/kg, i.p.), a selective 5-HT(1A)-receptor agonist. These findings suggest that perospirone may exhibit anti-OCD activity in clinical use and that 5-HT(1A)-receptor agonistic activity may be involved in the inhibition of marble-burying behavior by perospirone.     

Effect of paroxetine on marble-burying behavior in mice

The present study was undertaken to investigate the effect of paroxetine, a selective serotonin reuptake inhibitor (SSRI), on marble-burying behavior in mice in comparison with those of fluvoxamine and clomipramine. Marble-burying test is extensively used as an animal model for obsessive/compulsive disorder. A significant inhibition in marble-burying behavior was observed with paroxetine, at a dose of 10 mg/kg. The earlier SSRI, fluvoxamine, also significantly inhibited marble-burying behavior at a dose of 30 mg/kg. Although clomipramine, a tricyclic antidepressant, caused an inhibition in marble-burying behavior, a high dose of 100 mg/kg was needed to show a significant effect. On the other hand, all the drugs used in the present study showed no significant changes in spontaneous locomotor activity at doses inhibiting marble-burying behavior. In conclusion, it was confirmed that paroxetine has a potent inhibitory effect on marble-burying behavior in mice, and could have a similar antiobsessive/anticompulsive activity in human beings.     

Effects of mood stabilizers on marble-burying behavior in mice

Rationale

Obsessive–compulsive disorder (OCD) is characterized by recurrent unwanted thoughts (obsessions), usually accompanied by repetitive behaviors (compulsions) intended to alleviate anxiety. Marble-burying behavior is a pharmacological model for study of OCD.

Objectives

In the present study, we examined the effects of mood stabilizers on marble-burying behavior in mice, as well as the role of GABA receptors in this behavior.

Methods

The effects of treatment with valproate, carbamazepine, lithium carbonate, lamotrigine, muscimol and baclofen on marble-burying behavior in mice were evaluated.

Results

Valproate (10, 30 and 100 mg/kg, i.p.) and carbamazepine (30 and 100 mg/kg, p.o.) significantly reduced marble-burying behavior without affecting total locomotor activity in ICR mice. Lamotrigine (30 mg/kg, i.p.) also significantly reduced marble-burying behavior in ddY mice. On the other hand, lithium carbonate (10, 30 and 100 mg/kg, i.p.) reduced total locomotor activity without affecting marble-burying behavior in ddY mice. The selective GABA_A receptor agonist muscimol (1 mg/kg) significantly reduced marble-burying behavior without affecting total locomotor activity, whereas the selective GABA_B receptor agonist baclofen (3 mg/kg) reduced total locomotor activity without affecting marble-burying behavior. Moreover, the selective GABA_A receptor antagonist bicuculline (3 mg/kg) significantly counteracted the decrease in marble-burying induced by the administration of muscimol (1 mg/kg) and valproate (100 mg/kg).

Conclusions

These results suggest that GABAergic mechanism is involved in marble-burying behavior, and that valproate, carbamazepine and lamotrigine reduce marble-burying behavior. Moreover, valproate reduces marble-burying behavior via a GABA_A receptor-dependent mechanism.     

Combination of aripiprazole and ethanol attenuates marble-burying behavior in mice

Obsessive-Compulsive Disorder (OCD) is characterized by absurd, recurrent thoughts (obsessions) followed by certain stereotyped actions (compulsions). 5-Hydroxytryptamine (5-HT) abnormalities may be involved in OCD, and further, cause changes in serotonergic transmission that may have direct or indirect effects on the neuronal firing of other neuromodulators affecting thoughts, feelings and behaviors. Serotonin-related genes that are found in OCD include those coding for the 5-HT transporter (5-HTT) and receptors (5-HT(2A), 5-HT(2B), 5-HT(2C) and 5-HT(1B)) as well the 5-HT enzyme tryptophan hydroxylase. OCD can impair all areas of brain functioning and produce devastating effects on patients and their families. Marble-burying behavior of mice has been employed to study anxiety disorders, including the OCD. The aim of this study was to test the efficacy of aripiprazole and alcohol per se and in combination on marble-burying behavior of mice. A total of 114 male Swiss mice divided in 19 groups were studied. Aripiprazole (0.1 mg/kg, i.p.) per se as well as ethanol (0.1% w/v) per se did not show any anti-compulsive activity. But the combination comprising of ineffective doses of aripiprazole (0.1 mg/kg, i.p.) and ethanol (0.1% w/v) showed significant anti-compulsive activity as reflected by inhibition of marble-burying behavior.     

Role of serotonin type 1A receptors in fluvoxamine-induced inhibition of marble-burying behavior in mice

This study examined the roles of presynaptic and postsynaptic serotonin type 1A receptors in fluvoxamine-induced inhibition of marble-burying behavior in mice. The effect of fluvoxamine was attenuated by the serotonin type 1A receptor antagonist WAY100635 at 1 mg/kg, while it was enhanced by the antagonist at 0.1 mg/kg. Fluvoxamine (30 mg/kg) and WAY100635 (0.1 and 1 mg/kg) did not affect spontaneous locomotor activity. These results suggest that the effect of fluvoxamine is mediated by postsynaptic serotonin type 1A receptors and it is enhanced by an inhibition of presynaptic serotonin type 1A receptors.     

Role of 5-hydroxytryptamine2C receptors in marble-burying behavior in mice

We examined the role of 5-hydroxytryptamine(2C) (5-HT(2C)) receptors in marble-burying behavior in mice. When administered alone, the selective 5-HT(2C) agonist WAY161503 (3 mg/kg) inhibited marble-burying behavior. Moreover, the selective 5-HT(2C) antagonist SB242084 (3 mg/kg) reversed the inhibition of marble-burying behavior by 2,5-dimethoxy-4-iodoamphetamine (DOI) (1 mg/kg) or WAY161503 (3 mg/kg). Similarly, SB242084 (1 mg/kg) reversed the inhibition of marble-burying behavior by fluvoxamine (30 mg/kg) or paroxetine (3 mg/kg). These results suggest that 5-HT(2C) receptors play a role in marble-burying behavior in mice.     

Aripiprazole inhibits marble-burying behavior via 5-hydroxytryptamine (5-HT)1A receptor-independent mechanisms

Aripiprazole is a first next-generation atypical antipsychotic drug with dopamine system stabilizing, serotonin (5-hydroxytryptamine, 5-HT) 5-HT(1A) receptor partial agonistic, and 5-HT(2A) receptor antagonistic properties. In the present study, we examined the effect of aripiprazole on marble-burying behavior, which has been considered an animal model of obsessive-compulsive disorder, and compared this with the effects of other atypical antipsychotics such as olanzapine and quetiapine. Aripiprazole (1 mg/kg, i.p.) inhibited marble-burying behavior without affecting the locomotor activity in mice. Conversely, olanzapine (3 mg/kg, i.p.) and quetiapine (100 mg/kg, p.o.) showed significant suppression of locomotor activity and impairment of motor coordination at the dose that inhibited marble-burying behavior. On the other hand, a selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane (WAY100635, 3 mg/kg, i.p.) markedly antagonized the inhibition of marble-burying behavior by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 3 mg/kg, i.p.), a selective 5-HT(1A/7) receptor agonist. By contrast, WAY100635 at the same dose had no effect on the inhibition of marble-burying behavior by aripiprazole (1 mg/kg, i.p.). Quinpirole, a dopamine D(2) receptor agonist, showed significant suppression of locomotor activity at the dose that inhibited marble-burying behavior. Conversely, L-741,626, a selective dopamine D(2) receptor antagonist, at a dose of 10 mg/kg inhibited marble-burying behavior without affecting the locomotor activity. On the other hand, ketanserin, a 5-HT(2A) receptor antagonist, had no effect on the marble-burying behavior. These findings suggest that aripiprazole may be a useful drug for the treatment of obsessive-compulsive disorder, and that aripiprazole inhibits the marble-burying behavior via 5-HT(1A) receptor-independent mechanisms.     

LHRH antagonist attenuates the effect of fluoxetine on marble-burying behavior in mice

Leuprolide--a luteinizing hormone-releasing hormone (LHRH) agonist, dose dependently (100, 200 and 300 microg/kg, s.c.) inhibited marble-burying behavior in mice, which was comparable to that of fluoxetine (10 and 15 mg/kg, i.p.)--a drug used in the treatment of obsessive-compulsive disorder. Co-administration of sub-effective dose of leuprolide (50 microg/kg) and fluoxetine (5 mg/kg) significantly inhibited marble-burying-behavior. Pre-treatment with parachlorophenylalanine [300 mg/kg, i.p. (x3 days)]--a serotonin depleting agent, reversed the effect of fluoxetine, whereas partially attenuated the effect of leuprolide. Further, LHRH antagonist pre-treatment (2.5 microg/mouse, s.c.) completely blocked the effect of leuprolide and reduced the effect of fluoxetine. Motor activity remained unaffected after all treatments. In conclusion, the findings suggest that fluoxetine also implicates LHRH in its anti-compulsive effect.     

Involvement of the sigma1 receptor in inhibiting activity of fluvoxamine on marble-burying behavior: comparison with paroxetine

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.     

Stereospecific blockade of marble-burying behaviour in mice by selective, non-peptidergic neurokinin1 (NK1) receptor antagonists

By analogy with the selective serotonin reuptake inhibitor, fluvoxamine, and the tricyclic agent, clomipramine, the novel, selective, non-peptidergic NK(1) receptor antagonist, GR205,171, dose-dependently and completely blocked marble-burying behaviour in mice: Inhibitory Dose(50)s (ID(50)s), 4.5, 4.8 and 7.6 mg/kg, respectively. In contrast to GR205,171, its isomer, GR226,206, which displays substantially lower affinity for NK(1) receptors, was inactive (> 40.0 mg/kg). By analogy with GR205,171, a further, selective NK(1) antagonist, RP67,580, abolished marble-burying behaviour with an ID(50) of 11.9 mg/kg. At doses significantly reducing marble-burying behaviour, GR205,171 and RP67,580 little influenced motor behaviour. In conclusion, like fluvoxamine and clomipramine, selective, non-peptidergic NK(1) receptor antagonists block marble-burying in mice. Although the biological bases of this behaviour remain unclear, these observations underpin the contention that NK(1) receptors may be implicated in affective disorders.     

蛋白激酶C参与内源性大麻素1型受体对心肌L型钙电流的抑制作用

目的研究激活心肌内源性大麻素1型(CB1)受体是否通过改变蛋白激酶C(PKC)活性从而抑制L型钙电流,探讨激活CB1受体导致PKC活性变化的信号途径。方法利用酶解法制备大鼠心室肌细胞,分别单独应用CB1受体特异性激动剂2-氯乙胺花生四烯酸(ACEA)100 nmol·L-1、CB1受体阻断剂AM251 100 nmol·L-1或PKC非特异性激动剂十四烷酸乙酸大戟二萜醇酯(PMA)500 nmol·L-1孵育细胞10 min;此外提前应用AM251或PMA孵育细胞5 min后,再用ACEA孵育细胞10 min。应用全细胞膜片钳技术记录单个心肌细胞的L型钙电流;应用Pep Tag非放射性蛋白激酶C检测系统检测细胞PKC活性;ELISA试剂盒测定细胞中二酰甘油(DAG)的含量;Western蛋白印迹法测定磷脂酶Cβ(PLCβ)和磷酸化磷脂酶Cβ(p-PLCβ)表达。结果给予ACEA激动大鼠心肌细胞的CB1受体,可显著抑制L型钙电流,最大峰值电流密度由11.4±0.8降至(6.4±1.5)p A·p F-1;预先给予AM251或PMA可以完全阻断此抑制效应。检测心肌细胞PKC活性发现,与正常对照组(1.59±0.50)μmol·min-1·L-1相比,ACEA组心肌细胞PKC活性为(0.69±0.48)μmol·min-1·L-1,明显降低;同样预先给予AM251或PMA完全阻断ACEA对PKC活性的抑制效应。而给予ACEA没有影响心肌细胞DAG含量和PLCβ的磷酸化。结论激活心肌细胞CB1受体后抑制细胞PKC的活性,从而抑制L型钙电流,此过程没有PLCβ-DAG途径参与。     

Effects of glutamate-related drugs on marble-burying behavior in mice: implications for obsessive-compulsive disorder

Clinical evidence demonstrates altered glutamatergic neurotransmission in patients suffering from obsessive-compulsive disorder (OCD). We examined the effects of glutamate-related drugs on marble-burying behavior, which is an animal model of OCD. The uncompetitive N-methyl-d-aspartate (NMDA) antagonists memantine (10 mg/kg, i.p.) and amantadine (30 mg/kg, i.p.) significantly inhibited marble-burying behavior without affecting locomotor activity in mice. Similarly, the uncompetitive NMDA receptor antagonist 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine hydrogen maleate (MK-801, 0.3 mg/kg, i.p.) inhibited marble-burying behavior. However, MK-801 at the same dose markedly increased locomotor activity. By contrast, the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX) and the glutamate release inhibitor riluzole showed no effect on marble-burying behavior and significant suppression of locomotor activity. MK-801 (0.3 mg/kg, i.p.) and memantine (10 mg/kg, i.p.) significantly disrupted prepulse inhibition as an operational measure of sensorimotor gating. By contrast, amantadine (30 mg/kg, i.p.) did not affect prepulse inhibition. These findings suggest that amantadine could be a useful drug for the treatment of OCD.     

Deletion of vanilloid receptor (TRPV1) in mice alters behavioral effects of ethanol

The vanilloid receptor TRPV1 is activated by ethanol and this may be important for some of the central and peripheral actions of ethanol. To determine if this receptor has a role in ethanol-mediated behaviors, we studied null mutant mice in which the Trpv1 gene was deleted. Mice lacking this gene showed significantly higher preference for ethanol and consumed more ethanol in a two-bottle choice test as compared with wild type littermates. Null mutant mice showed shorter duration of loss of righting reflex induced by low doses of ethanol (3.2 and 3.4 g/kg) and faster recovery from motor incoordination induced by ethanol (2 g/kg). However, there were no differences between null mutant and wild type mice in severity of ethanol-induced acute withdrawal (4 g/kg) or conditioned taste aversion to ethanol (2.5 g/kg). Two behavioral phenotypes (decreased sensitivity to ethanol-induced sedation and faster recovery from ethanol-induced motor incoordination) seen in null mutant mice were reproduced in wild type mice by injection of a TRPV1 antagonist, capsazepine (10 mg/kg). These two ethanol behaviors were changed in the opposite direction after injection of capsaicin, a selective TRPV1 agonist, in wild type mice. The studies provide the first evidence that TRPV1 is important for specific behavioral actions of ethanol.     

让合理、安全用药知识(五十二) 走进千家万户

(接上期)四、抗心绞痛药2.单硝酸异山梨酯(5-单硝酸异山梨醇、5-单硝酸异山梨醇酯、5-单硝酸异山梨酯、长效心痛治、异乐定)新一代长效硝酸酯类抗心绞痛药,作用机制与硝酸甘油相同,但作用时间较长。临床用于:1.用于冠心病的长期治疗;预防劳累性心绞痛、变异型心绞痛及混合     

Anxiolytic-like activity of MGS0039, a potent group II metabotropic glutamate receptor antagonist, in a marble-burying behavior test

Glutamatergic abnormalities are involved in several psychiatric disorders. Clinical evidence demonstrates altered glutamatergic neurotransmission in patients suffering from obsessive-compulsive disorder. MGS0039, (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, is a novel group II metabotropic glutamate (mGlu) receptor antagonist. We examined MGS0039's potential anti-obsessive-compulsive disorder activity, using the marble-burying behavior test as a model of obsessive-compulsive disorder. MGS0039 as well as LY341495 ((2S,1'S,2'S)-2-(9-xanthylmethyl)-2-(2'-carboxycycloprolyl)glycine), another group II mGlu receptor antagonist, inhibited marble-burying behavior. We also demonstrated that this effect was significantly attenuated by a group II mGlu receptor agonist. This data indicates that group II mGlu receptor antagonists may exert anti-obsessive-compulsive disorder effects in clinical use.     

Capsaicin receptor: TRPV1 a promiscuous TRP channel

TRPV1, the archetypal member of the vanilloid TRP family, was initially identified as the receptor for capsaicin, the pungent ingredient in hot chili peppers. The receptor has a diverse tissue distribution, with high expression in sensory neurons. TRPV1 is a nonselective cation channel with significant permeability to calcium, protons, and large polyvalent cations. It is the most polymodal TRP channel, being activated by numerous stimuli, including heat, voltage, vanilloids, lipids, and protons/cations. TRPV1 acts as a molecular integrator of physical and chemical stimuli in peripheral nociceptor terminals and plays a critical role in thermal inflammatory hyperalgesia. In addition, TRPV1 may regulate a variety of physiological functions in different organ systems. Various second messenger systems regulate TRPV1 activity, predominantly by serine-threonine phosphorylation. In this review, we provide a concise summary of the information currently available about this channel.     

Increased marble-burying behavior in ethanol-withdrawal state: modulation by gonadotropin-releasing hormone agonist

A characteristic behavior in alcohol abstinence state indicates the possibility of obsessive-compulsive behavior in alcoholics. Ethanol is known to reduce hypothalamic synthesis, release, and mRNA expression of gonadotropin-releasing hormone (GnRH) that modulates serotonergic, dopaminergic, and glutamatergic systems, which experience adaptive changes on chronic exposure to ethanol. Such changes are also evident in obsessive-compulsive disorder. Therefore, it was proposed to investigate the effect of ethanol-withdrawal on marble-burying behavior in mice, particularly because it simulates some aspects of obsessive-compulsive behavior; further, the influence of GnRH agonist was studied on the same. Ethanol-withdrawal state was induced after its chronic administration, and marble-burying behavior was observed at 0, 6, 24, 48, and 96 h interval. Further, the influence of leuprolide--a GnRH agonist (50-600 microg/kg, s.c.) or fluoxetine (5-30 mg/kg, i.p.) was investigated on ethanol-withdrawal-induced changes in marble-burying behavior. The results indicated that ethanol-withdrawal led to a gradual increase in marble-burying behavior upto 48 h with peak at 24 h interval. Administration of leuprolide (100-600 microg/kg, s.c.), 30 min prior to 24 h interval, dose dependently reduced ethanol-withdrawal-induced increase in marble-burying behavior, and this effect was comparable to that of fluoxetine (15 and 30 mg/kg, i.p.). Further, twice daily administration of leuprolide (50 microg/kg, s.c), concomitant with ethanol, prevented the gradual increase in marble-burying behavior after ethanol-withdrawal and this effect was comparable to fluoxetine (5 mg/kg, i.p.). In conclusion, ethanol-withdrawal on chronic administration increases marble-burying behavior in mice; its development and expression is attenuated by leuprolide.