Attenuation of induced-anxiety in rats by chlordiazepoxide: Role of raphe dorsalis benzodiazepine binding sites and serotoninergic neurons

doi:10.1016/0306-4522(82)90139-7

Neuroscience

Volume 7, Issue 9, September 1982, Pages 2287-2294

https://doi.org/10.1016/0306-4522(82)90139-7 Get rights and content

Abstract

In chronically implanted awake rats, microinjections of chlordiazepoxide (5 × 10⁻⁷M) into the dorsal raphésignificantly attenuated the inhibition of lever-pressing for food elicited by a signal of punishment. This effect is abolished by prior application of 5,7-dihydroxytryptamine into the dorsal raphé(3 weeks after the infusion of the neurotoxin, dorsal raphétryptophan hydroxylase activity was reduced to 25% of control values). Furthermore, the disinhibitory effect of intra raphéchlordiazepoxide can be mimicked or potentiated by intra raphédorsalis application of serotonin (10⁻⁷ or 10⁻⁸ M, respectively). Further evidence for a crucial interaction between benzodiazepines and serotoninergic processes are provided by in vitro experiments showing that chlordiazepoxide or diazepam (10⁻⁵ M) are able to facilitate the K⁺ -evoked [³H]serotonin release from rat midbrain slices. Finally, a high density of [³H]flunitrazepam binding sites was found in the dorsal (and the median) raphénucleus, the Kd and B_max values being not altered by prior infusion of 5,7-dihydroxytryptamine.

These in vitro data suggest possible means by which intra raphé(and perhaps peripherally administered) benzodiazepines may affect the activity of serotoninergic neurons and thereby produce their effects on experimental anxiety.

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- 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.

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Attenuation of induced-anxiety in rats by chlordiazepoxide: Role of raphe dorsalis benzodiazepine binding sites and serotoninergic neurons

Abstract

Eur. J. Pharmac.

Brain Res.

Pharmac. Biochem. Behav.

Brain Res.

Brain Res.

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Physiol. Behav.

Pharmac. Biochem. Behav.

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Biochem. Pharmac.

Life Sci.

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Neuroscience

J. biol. Chem.

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Neuroscience

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Pharmac. Biochem. Behav.

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Neuropharmacology