In Vivo High Intrinsic Efficacy of Triazolam: A Positron Emission Tomography Study in Nonhuman Primates
Abstract
Abstract:The triazolobenzodiazepine triazolam is a central‐type benzodiazepine receptor (BZR) ligand that is widely prescribed as a hypnotic agent. Triazolam produces its effects through potentiation of γ‐aminobutyric acid‐mediated neurotransmission. Findings reported from in vitro binding studies showed some discrepancies concerning the pharmacological characteristics of triazolam. The present study aims to characterize in vivo the biochemical properties of triazolam, i.e., cerebral pharmacokinetics, interaction with BZR, potency, and intrinsic efficacy. Triazolam was studied in living nonhuman primates using positron emission tomography. Two different studies were carried out: (a) a direct study using [11 C]triazolam and (b) an indirect competition study using the radiolabeled BZR antagonist [11 C]flumazenil. Results showed that, in the brain in vivo, triazolam binds specifically and competitively to the BZR. Its rapid cerebral kinetics is consistent with a hypnotic profile (maximal binding after 23 min, elimination half‐life of 202 min). Triazolam is very potent in displacing [11 C]flumazenil (ID 50= 28 ± 6 μg/kg). Hill analysis of the displacement curve does not show obvious binding‐site heterogeneity. Triazolam is 20 times more potent in displacing [11 C]flumazenil and 50 times more potent in inhibiting pentylenetetrazol‐induced paroxysmal activity than the full benzodiazepine agonist diazepam. Interestingly, the simultaneous use of positron emission tomography and EEG recording allowed us to show that triazolam‐positive intrinsic efficacy is slightly higher (20%) than that of diazepam. An attractive hypothesis proposes that the severity of side effects of BZR ligands is proportional to their intrinsic efficacy. Therefore, our study shows that triazolam side effects, as for other benzodiazepines, may be related to its high intrinsic efficacy in vivo.
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Seizure threshold shows a hyperbolic relationship to benzodiazepine dose in zebrafish, rats, and non-human primates.
“Seizure threshold shows a hyperbolic relationship to dose in zebrafish (Gupta, Khobragade, & Shingatgeri, 2014), rats (Kapur & Macdonald, 1997), and non-human primates (Bottlaender et al., 1994) (Figure 3b).”
From Pharmacological principles for safe benzodiazepine and Z-drug dose reduction (2026) · cites this paper as Bottlaender et al., 1994
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“Seizure threshold shows a hyperbolic relationship to dose in zebrafish (Gupta, Kho-bragade, & Shingatgeri, 2014), rats (Kapur & Macdonald, 1997), and non-human primates (Bottlaender et al., 1994) (Figure 3b).”
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- Authors
- Bottlaender, M., Brouillet, E., Varastet, M., Le Breton, C., Schmid, L., Fuseau, C., Sitbon, R., Crouzel, C., & Mazière, M.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Mazière, Mariannick
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 1994-03
- Volume
- 62
- Issue
- 3
- Pages
- 1102-1111
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2014509544
- Cited by
- 17
- References
- 47
- Citations by year
- 2026: 1 · 2024: 1 · 2018: 1 · 2016: 1 · 2014: 1 · 2013: 1
- FWCI
- 0.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and pharmacology of benzodiazepine derivatives
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- triazolam, benzodiazepine receptor, intrinsic efficacy, [11C]flumazenil, receptor binding, hypnotics, diazepam, pentylenetetrazole-induced seizures, non-human primates
- MeSH terms
- Animals, Anticonvulsants, Blood, Brain, Flumazenil, Ligands, Male, Papio, Receptors, GABA-A, Tomography, Emission-Computed, Triazolam
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