Effect of diazepam on fate of intracisternally injected serotonin-C14

doi:10.1016/0028-3908(70)90053-5

Neuropharmacology

Volume 9, Issue 2, March 1970, Pages 103-108

https://doi.org/10.1016/0028-3908(70)90053-5 Get rights and content

Abstract

The influence of diazepam on the disposition of intracisternally injected serotonin-C¹⁴ (5-HT-C¹⁴) was studied in the rat. Pretreatment with diazepam failed to affect the uptake of this monoamine into brain. Whole brain levels of 5-HT-C¹⁴ and 5-hydroxyindoleacetic acid-C¹⁴ (5-HIAA-C¹⁴), substantially above control levels, were found in diazepam-treated rats killed three hours after 5-HT-C¹⁴ administration. The drug markedly retarded the efflux of intracisternally administered 5-HIAA-C¹⁴ but had no effect on metaraminol-H³, a monoamine which is not metabolized in brain. These findings suggest that diazepam may act on mechanisms subserving the transport of 5-HIAA from brain as well as on the cerebral metabolism of 5-HT.

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2005, Pharmacology Biochemistry and Behavior
This study utilized a novelty-induced suppression of feeding task to examine anxiety-like behaviour and the anxiolytic effects of the 5-HT_1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), in rats prenatally exposed to ethanol. Adult offspring from ethanol exposed (E), pair-fed control (PF) and ad libitum-fed control (C) dams were habituated to a novel palatable food for 21 days and measures of baseline feeding obtained. On day 22 (d 22), animals received either 8-OH-DPAT (0.06 mg/kg) or vehicle (0.9% NaCl) and feeding behaviour in the home cage or a novel cage was observed. Factor analyses revealed that feeding behaviour on d 21 (habituation) and d 22 (test day) are reflective of two different affective states, and that the single factor that emerged for novel cage testing on d 22 likely reflects the anxiety evoked by the novel test condition. Analyses of variance on the variables loading significantly onto the factors support the suggestion that the novel environment is anxiogenic for both females and males, and that 8-OH-DPAT acts as an anxiolytic. However, although both females and males showed alterations in behaviours (latency, amount, duration of feeding) reflective of anxiety, 8-OH-DPAT had anxiolytic effects primarily in females. Importantly, prenatal ethanol exposure altered several aspects of behavior in this task. Both E females and males consumed less than their control counterparts on d 21, suggesting a possible delay or deficit in response habituation. During home cage testing on d 22, overall feeding rate was slower in E than in C females, and E males consumed less than PF and C males. In addition, a smaller percentage of E than PF and C females fed in the novel environment, and latency to feed was significantly increased in E compared to control females. These findings indicate that prenatal ethanol exposure results in increased anxiety-like behaviour in adulthood, and that prenatal ethanol-induced hyponeophagia may be, at least in part, mediated by the 5-HT_1A receptor. This study is one of the first to demonstrate specific increases in anxiety-like behaviour in animals prenatally exposed to ethanol, and further supports the utility of the novelty-induced suppression of feeding task in assessing anxiety and the effectiveness of anxiolytic agents.
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FERNÁNDEZ-GUASTI, A. AND C. LÓPEZ-RUBALCAVA. Modification of the anxiolytic action of 5-HT_1A compounds by GABA–benzodiazepine agents in rats. PHARMACOL BIOCHEM BEHAV 60(1) 27–32, 1998.—The general purpose of the present study was to analyze the possible interactions between the GABA–benzodiazepine and the serotonin systems in the mediation of the antianxiety actions of 5-HT_1A compounds. The anxiolytic effect of buspirone (5 mg/kg), ipsapirone (5 mg/kg), indorenate (5 mg/kg), and 8-OH-DPAT (0.5 mg/kg) was established in the rat burying behavior test. Flumazenil (5 mg/kg), but not bicuculline (2.5 mg/kg), effectively counteracted the reduction in burying behavior produced by buspirone, ipsapirone, and 8-OH-DPAT. These same 5-HT_1A compounds, at subthreshold doses, produced an important reduction in burying behavior when combined with diazepam (0.25 mg/kg). The effect of indorenate was not altered by any of the antagonists and, when combined with diazepam it produced large increases in burying behavior latency. Only buspirone alone and in combination with bicuculline or flumazenil impaired motor coordination as tested in the rota rod. Data are discussed on the bases of the interaction between the GABAergic and serotonergic systems, stressing species differences and variations due to the animal model of anxiety.
Alprazolam, diazepam, yohimbine, clonidine: In vivo CA<inf>1</inf> hippocampal, norepinephrine and serotonin release profiles under chloral hydrate anesthesia
1997, Progress in Neuro-Psychopharmacology and Biological Psychiatry
- 1.
  1. Although the GABA-A receptor complex has been the main focus of anti-anxiety therapy, the neural interaction in the septohippocampal circuit between GABA-A and the neurotransmitter, 5-HT, compels a study of the monoamine, 5-HT, in anxiety as well.
- 2.
  2. Neurochemistry for anxiety is also intimately involved with the nEurotransmitter, Ne. Indeed, 5-HT is a component of the dorsal ascending noradrenergic bundle and both neurotransmitters, NE and 5-HT, have been implicated in clinical depression.
- 3.
  3. In vivo microvoltammetric studies were performed using miniature carbon based sensors to detect NE release and concurrent 5-HT release, with 2 separate neural electrochemical signals, within CA₁ region of hippocampus, in the chloral hydrate anesthetized rat.
- 4.
  4. Time course studies showed that both the triazolobenzodiazepine (TBZD), alprazolam, and the benzodiazepine (BZD), diazepam, decreased hippocampal NE release.
- 5.
  5. The in vivo and $online$ neurochemical profile of hippocampal 5-HT release for alprazolam differed from that of Diazepam I.e. alprazolam increased hippocampal 5-HT release, whereas diazepam decreased hippocampal 5-HT release.
- 6.
  6. Time course studies showed that the a₂-adrenergic antagonist, yohimbine, an anxiogenic agent, increased both NE and 5-HT release in CA₁ region of hippocampus; the a₂-adrenergic agonist, clonidine, decreased NE release and increased 5-HT release in the same region.
- 7.
  7. Neither the profile for the TBZD, alprazolam, nor that of the BZD, diazepam, mimicked the neurochemical profile for the anxiogenic agent, yohimbine; the neurochemical profile for the TBZD, alprazolam, was similar to that of the a₂-adrenergic agonist, clonidine.
- 8.
  8. Interestingly, alprazolam's hippocampal 5-HT/NE interaction is similar to clonidine's 5-HT/NE action at a₂-adrenergic autoreceptors, resulting in enhanced 5-HT release.
- 9.
  9. Enhanced 5-HT release in hippocampus, exhibited by the atypical TBZD, alprazolam, and not by the typical BZD, diazepam, may be an underlying mechanism for the antidepressant activity exhibited by alprazolam.
Future directions in anxiolytic pharmacotherapy
1995, Psychiatric Clinics of North America
Pharmacologists have been searching for new anxiolytic drugs that are fast acting and free from the unwanted side effects associated with the traditional benzodiazepines through two major approaches. The first approach entails the discovery of compounds that act as partial agonists at benzodiazepine receptors, which, in turn, are linked to GAB A-A receptors. The second approach is based on recent experimental findings that demonstrate the role of multiple additional neurotransmitters and neuropeptides in the neurobiology of anxiety. This article provides an overview of recent developments based on both these approaches and offers a glimpse of new potential anxiolytic therapies.
Interaction of GABA and serotonin in the anxiolytic action of diazepam and serotonergic anxiolytics
1992, Pharmacology, Biochemistry and Behavior
The general purpose of the present study was to analyze the possible interactions between the GABA-benzodiazepine and the serotonergic (5-HT) systems in the anxiolytic action of diazepam and the 5-HT_1A agonists, ipsapirone, indorenate, and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The effect of the benzodiazepine receptor antagonist, flumazenil (10.0 mg/kg), on the anxiolytic action of ipsapirone (5.0 mg/kg), indorenate (5.0 mg/kg), and 8-OH-DPAT (0.125 mg/kg) was examined on the avoidance exploratory behavior paradigm in mice. The effect of the 5-HT₁ blockers, methiotepin (0.31 mg/kg), pindolol (3.1 mg/kg), and alprenolol (5.0 mg/kg), on the anxiolytic action of diazepam (0.5 mg/kg) was also studied. In the last part of this work, the putative potentiation between diazepam (0.25 mg/kg) and each of the serotonergic anxiolytics was investigated. The antianxiety effect of diazepam, ipsapirone, indorenate, and 8-OH-DPAT was prevented by flumazenil. The serotonergic/β-blocker, alprenolol, partially antagonized the diazepam effect. Finally, a potentiation of suboptimal doses of diazepam and ipsapirone, but not with indorenate or 8-OH-DPAT, was observed. The findings suggest an interaction between both systems on the anxiolytic action of diazepam and the 5-HT_1A agonists.
Benzodiazepines impair a behavioral effect induced by stimulation of 5-HT1B receptors
1990, Pharmacology, Biochemistry and Behavior
Seven days of isolation induce in mice a social behavioral deficit (decrease in escape attempts) reversed by TFMPP acting through activation of HT1B receptors. The present experiments were performed to investigate the interaction between tranquillizing drugs and one aspect of the serotonergic functioning through the TFMPP-induced increase in escape attempts. The benzodiazepines diazepam, alprazolam, triazolam and chlordiazepoxide impaired significantly TFMPP-induced increase in escape attempts at behaviorally inactive doses. Buspirone opposed TFMPP effect, but the active doses 4 and 16 mg/kg alone decreased the number of escape attempts. ICS 205-930 in a large dose range (0.001–1 mg/kg) modified neither the number of escape attempts nor the increase induced by TFMPP. Chronic (11 days) treatment with buspirone (16 mg/kg) or ICS 205-930 (1 mg/kg) modified neither the number of escape attempts of isolated mice nor the increase induced by TFMPP. These results suggest that tranquillizing drugs of the benzodiazepines group, but not of other groups, interact with the 5-HT1B receptors; they add to knowledge of relations between benzodiazepines and serotonin by specifying the involvement of 5-HT1B receptors.

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Effect of diazepam on fate of intracisternally injected serotonin-C14

Abstract

Life Sci.

Biochem. Pharmac.

Life Sci.

Adv. Pharmac.

Jap. J. Pharmac.

J. Pharm. Sci.

Life Sci.

Life Sci.

Biochem. Pharmac.

Biochem. Pharmac.

Biochem. Pharmac.

Adv. Pharmac.

Localization of tritiated serotonin in rat brain by electron-microscopic autoradiography

J. Pharmac. exp. Ther.

Influence de trois I.M.A.O. sur le choc pentetrazolique chez le lapin

Therapie

An improved method for the fluorimetric determination of 5-hydroxytryptamine in tissues

Acta physiol. scand.

Brain 5-hydroxytryptamine and anticonvulsant activity

J. Pharmac. exp. Ther.

Anticonvulsant properties of chlordiazepoxide, diazepam and certain other 1,4-benzodiazepines

Archs int. Pharmacodyn. Thér.

Effect of diazepam on fate of intracisternally injected serotonin-C¹⁴