Anxiogenic effects of methyl-β-carboline-3-carboxylate in a light/dark choice situation

doi:10.1016/0091-3057(87)90006-2

Pharmacology Biochemistry and Behavior

Volume 28, Issue 1, September 1987, Pages 29-33

https://doi.org/10.1016/0091-3057(87)90006-2 Get rights and content

Abstract

Doses of benzodiazepine, clorazepate, and also of the inverse agonist of the benzodiazepine receptor, β-CCM, which failed to present sedative or postictal depressive effects, were at first determined in a free exploratory situation. Then, the effects of clorazepate dosed at 1.0, 2.0 and 4.0 mg/kg and β-CCM dosed at 1.0 and 2.5 mg/kg were studied in the light/dark box choice procedure. Clorazepate tended to produce an increase of the time spent by mice in the lit box as well as of the number of transitions between the two boxes, whereas the dose of 1.0 mg/kg of β-CCM had opposite effects. The benzodiazepine antagonist RO 15-1788 completely counteracted the anxiolytic effects of clorazepam dosed at 2.0 mg/kg and the anxiogenic effects of β-CCM.

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The test subject is placed in the brightly-illuminated chamber and allowed to move freely between the two compartments. The amount of time spent in the dimly-lit chamber (Hascoët and Bourin, 1998) and the number of transitions between the chambers (Belzung et al., 1987; Bourin and Hascoët, 2003) are used as measures of anxiety-like behavior. Previous studies have shown that the anxiety-like behaviors of most rodents remain stable with repeated exposure to the L/D test apparatus at various inter-test intervals.
Behavioral phenotyping has been gaining prominence due to the increased use of transgenic animal models of neurological disorders. Repeated testing in the same cohort of animals can reduce the overall number of animals used and is desired especially when animal numbers are difficult to obtain as well as for studies involving within-subject design such as drug treatments or aging. This review aims to provide researchers with a comprehensive overview of the carryover effects when subjecting the same set of animals to the same behavioral test. We have focused on three behavioral domains of testing: anxiety, cognition and depression. Based on a review of the literature and our own experiences as a neurobehavioral core facility, we have found that manipulating inter-test interval, environmental contextual cues and stimuli can mitigate the carryover effects to a large extent, although there are certain tests that still show strong residual effects. In addition, the effects of strain on carryover effects from repeated testing are also discussed in this review.
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Sodium nitroprusside (SNP) is a nitric oxide (NO) donor which actually is under assessment as a potential candidate for the treatment of schizophrenia. It is well documented that anxiety symptoms are a prominent future in various psychiatric diseases comprising schizophrenia. Prior research has shown that acute challenge with SNP (1–3 mg/kg) induced anti-anxiety effects in rats but these effects at high doses were confounded by sedation and were disappeared after repeated application of it. It is still unknown if administration of a lower SNP dose range, either acutely or sub-chronically, could induce anxiolytic-like behaviour. The present study was designed to investigate this issue in rats. For this aim, the light/dark and the open field tests were used. Acute challenge with SNP (0.1 and 0.3 mg/kg, 30 min before testing) did not affect rodents' performance in the above mentioned behavioural paradigms. Conversely, rats treated sub-chronically with SNP (0.1 and 0.3 mg/kg, once per day, for 5 consecutive days), displayed longer time spent in the light chamber of the light/dark box and in the central area of the open field with respect to their vehicle-treated counterparts. Interestingly, SNP did not influence the first latency to enter the dark chamber and the number of transitions between the light and dark compartments of the apparatus in the light/dark test and did not modify the number of squares crossed, grooming episodes and rearings in the open field test. Finally, acute administration of SNP (0.1, 0.3 and 1 mg/kg, 10 min before testing) also did not influence rats’ performance in the light/dark test. The present results indicate that short-term repeated but not acute application of a range of low doses of the NO donor SNP in a dose-independent manner induced an anti-anxiety behaviour in the rat which was not accompanied by undesired effects.
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In the course of our continuing exploration for novel bioactive lead compounds (s) from the species Boswellia, we have recently reported incensole derivatives isolated from Boswellia papyrifera Hochst. Given the known antidepressant-like effects of incensole and incensole acetate, we herein present that the low dose intraperitoneal administration of incensole derivatives, namely, incensfuran and incensone, showed significant antidepressant-like effects in the forced swim test (FST) and tail suspension test (TST). Furthermore, these compounds were evaluated for their anxiolytic potential in the elevated plus maze (EPM) and light dark box (LDB) tests and anticonvulsant effects in pentylenetetrazole (PTZ)-induced seizure tests. In the EPM test, administration of these compounds led to dose-dependent increases in open arm entries and in the time spent in EPM open arms. Similar results were obtained in the LDB test, wherein compounds these caused significant increases in the number of transitions between lit and dark compartments and the time spent in the lit compartment. The anxiolytic-like effects in the EPM were not reversed by pretreatment with flumazenil, whereas PTZ and bicuculline (BIC) completely abolished the anxiolytic effects, showing the involvement of the non-benzodiazepine binding sites of GABA_A receptors. All four compounds induced significantly elevated brain GABA levels, indicating the involvement of a GABAergic mechanism. Additionally, molecular docking was conducted to elucidate the mode of action for the anxiolytic and anticonvulsant effects of these derivatives. Moreover, these compounds also possess drug-like properties and excellent ADMET profiles.
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Our previous study found that serotonin 1A receptor (5-HT1aR) is an endogenous suppressor of nNOS expression in the hippocampus, which accounts for anxiolytic effect of fluoxetine. However, the precise molecular mechanism remains unknown. By using 8-OH-DPAT, a selective 5-HT1aR agonist, NAN-190, a selective 5-HT1aR antagonist, and U0126, an Extracellular Regulated Protein Kinases (ERK) phosphorylation inhibitor, we investigated the role of ERK in 5-HT1aR-nNOS pathway. Western blots analysis demonstrated that 5-HT1aR activation up-regulated the level of phosphorylated ERK (P-ERK) beginning at 5 min and down-regulated the expression of nNOS beginning at 20 min. Meanwhile, blockage of 5-HT1aR resulted in a decrease in P-ERK beginning at 20 min and caused an increase in nNOS expression beginning at 6 h. Although U0126 itself did not alter nNOS expression and activity, NO level, and anxiety-related behaviors, the treatment totally reversed 8-OH-DPAT-induced reduction in nNOS expression and function, and anxiolytic effect. Besides, our data showed that ERK phosphorylation was essential for 5-HT1aR activation-induced cAMP responsive element binding protein (CREB) phosphorylation, hippocampal neurogenesis and synaptogenesis of newborn neuron. Our study suggests a crucial role of ERK phosphorylation in the regulation of nNOS expression by 5-HT1aR, which is helpful for understanding the mechanism of 5-HT1aR-based anxiolytic treatment.
Acute and repeated exposure with the nitric oxide (NO) donor sodium nitroprusside (SNP) differentially modulate responses in a rat model of anxiety
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This test has the advantages of being quick and easy to use without prior training of the animals, and neither food nor water deprivation are required [3]. Transitions in this test are considered an index of activity/exploration because habituation over time is seen with this measure, whereas the time spent in each compartment reflects aversion/attraction [1]. Drugs that affect general motor function may affect performance in anxiety tests because of changes in motoric activity that are unrelated to any anxiogenic- or anxiolytic-like effects of the compound.
The nitric oxide (NO) donor sodium nitroprusside (SNP) actually is under investigation for the treatment of schizophrenia. That anxiety disorders are noted to occur commonly in schizophrenia patients is known. Contradictory results were reported however, concerning the effects of SNP in animal models of anxiety disorders. The present study investigated the effects of acute and repeated administration of SNP on anxiety-like behaviour in rats assessed in the light/dark test. The effects of SNP on motility in a locomotor activity chamber were also investigated in rats. Acute administration of 1 mg/kg SNP 30 but not 60 min before testing induced anxiolytic-like behaviour which cannot be attributed to changes in locomotor activity. Conversely, a single injection of 3 mg/kg SNP at 30 min before testing depressed rats' general activity, while at 60 min this dose did not influence performance of animals either in the light/dark or in the motor activity test. Repeated application of SNP (1 and 3 mg/kg, for 5 consecutive days) did not alter rodents' performance in the above described behavioural paradigms. The present results suggest that the effects exerted by SNP in the light/dark test in rats are dose, time and treatment schedule-dependent. The current findings propose also a narrow therapeutic window for SNP in this animal model of anxiety.
The nitric oxide donor molsidomine induces anxiolytic-like behaviour in two different rat models of anxiety
2015, Pharmacology Biochemistry and Behavior
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This test has the advantages of being quick and easy to use without prior training of the animals, and neither food nor water deprivation is required (Bourin and Hascoet, 2003). Transitions in this test are considered an index of activity/exploration because habituation over time is seen with this measure, whereas the time spent in each compartment reflects aversion/attraction (Belzung et al., 1987). Administration of 2 mg/kg, but not 1 or 4 mg/kg, of molsidomine in rats increased the time spent in the light compartment compared with their control cohorts.
Experimental evidence indicates the implication of the nitric oxide (NO) in anxiety. Contradictory results were reported however, concerning the effects of NO donors in animal models of anxiety disorders. The present study investigated the effects of the NO donor molsidomine on anxiety-like behaviour and compared them with the anxiolytic diazepam in rats. For this purpose, the light/dark and the open field tests were used. The effects of molsidomine on motility were also assessed. Intraperitoneal (i.p.) administration of molsidomine (1 and 4 mg/kg) did not influence rats' performance either in the light/dark or in the open field test. Administration of 2 mg/kg molsidomine significantly prolonged the time spent in the light chamber in the rats compared with the vehicle-treated animals, did not affect the first latency to enter the dark chamber and did not influence the number of transitions between the light and dark compartments of the apparatus. In the open field test, rats that received 2 mg/kg molsidomine spent more time in the central zone of the apparatus and exhibited an increment of rearing episodes compared with control and to molsidomine 1 and 4 mg/kg-treated rats. Nevertheless, molsidomine, at any dose tested, did not alter locomotor activity compared with vehicle-treated rats in a motility test. The present results indicate that the 2 mg/kg molsidomine induced anxiolytic-like effects in the light/dark and open field tests in the rat cannot be attributed to changes in locomotor activity. The magnitude of the molsidomine (2 mg/kg)-induced anxiolytic-like effects was not different to that produced by the benzodiazepine anxiolytic diazepam (1 mg/kg).

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Anxiogenic effects of methyl-β-carboline-3-carboxylate in a light/dark choice situation

Abstract

Pharmacol Biochem Behav

Neuropharmacology

Pharmacol Biochem Behav

Pharmacol Biochem Behav

Neuropharmacology

Neuropharmacology

Neurosci Lett

Pharmacol Biochem Behav

Life Sci.

Anim Behav

Psychoneuroendocrinology

Pharmacol Biochem Behav