Benzodiazepine | EPFL Graph Search

Benzodiazepines (BZD, BDZ, BZs), colloquially called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, insomnia, and seizures. The first benzodiazepine, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955 and was made available in 1960 by Hoffmann–La Roche, who soon followed with diazepam (Valium) in 1963. By 1977, benzodiazepines were the most prescribed medications globally; the introduction of selective serotonin reuptake inhibitors (SSRIs), among other factors, decreased rates of prescription, but they remain frequently used worldwide. Benzodiazepines are depressants that enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABAA receptor, resulting in sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, and muscle relaxant pr

Diazepam actions in the VTA enhance social dominance and mitochondrial function in the nucleus accumbens by activation of accumbal dopamine D1 receptors

Sonia Abad Florensa, Carlos Canto Alvarez, Jocelin Grosse, Marie-Isabelle Guillot de Suduiraut, Fiona Hollis, Laura Lozano Montes, Maria del Carmen Sandi Perez, Michael van der Kooij, Ioannis Zalachoras, Olivia Zanoletti

Benzodiazepines can ameliorate social disturbances and increase social competition, particularly in high-anxious individuals. However, the neural circuits and mechanisms underlying benzodiazepines’ effects in social competition are not understood. Converging evidence points to the mesolimbic system as a potential site of action for at least some benzodiazepine-mediated effects. Furthermore, mitochondrial function in the nucleus accumbens (NAc) has been causally implicated in the link between anxiety and social competitiveness. Here, we show that diazepam facilitates social dominance, ameliorating both the competitive disadvantage and low NAc mitochondrial function displayed by high-anxious rats, and identify the ventral tegmental area (VTA) as a key site of action for direct diazepam effects. We also show that intra-VTA diazepam infusion increases accumbal dopamine and DOPAC, as well as activity of dopamine D1- but not D2-containing cells. In addition, intra-NAc infusion of a D1-, but not D2, receptor agonist facilitates social dominance and mitochondrial respiration. Conversely, intra-VTA diazepam actions on social dominance and NAc mitochondrial respiration are blocked by pharmacological NAc micro-infusion of a mitochondrial complex I inhibitor or an antagonist of D1 receptors. Our data support the view that diazepam disinhibits VTA dopaminergic neurons, leading to the release of dopamine into the NAc where activation of D1-signaling transiently facilitates mitochondrial function, that is, increased respiration and enhanced ATP levels, which ultimately enhances social competitive behavior. Therefore, our findings critically involve the mesolimbic system in the facilitating effects of diazepam on social competition and highlight mitochondrial function as a potential therapeutic target for anxiety-related social dysfunctions

Nature Publishing Group2018

GABA A receptors in the ventral tegmental area control the outcome of a social competition in rats

Maria del Carmen Sandi Perez, Michael van der Kooij, Ioannis Zalachoras

Social dominance can be attained through social competitions. Recent work in both humans and rodents has identified trait anxiety as a crucial predictor of social competitiveness. In addition, the anxiolytic GABAA positive modulator, diazepam, injected either systemically or into the ventral tegmental area (VTA) was shown to increase social dominance. Here, we investigated the impact of pharmacologically targeting GABAA receptors in the VTA for the outcome of a social competition between two unfamiliar male rats, one of them infused with vehicle and the other one with the drug under study. We show that infusion of the GABAA receptor agonist, muscimol, reduced anxiety-like behaviors and enhanced social competition, the GABAA receptor antagonist, bicuculline had the opposite effects. Importantly, intra-VTA muscimol administration also counteracted the disadvantage of high anxious rats to win a social competition against low anxious rats. Furthermore, we assessed the effectiveness of targeting specific GABAA receptor subunits by infusing zolpidem (α1-subunit agonist) or TCS1105 (a benzodiazepine ligand with α2-subunit agonistic and α1-subunit antagonistic effects) into the VTA. While zolpidem infusion did not affect the outcome of the social competition, TCS1105 enhanced social dominance. Our data highlight GABAergic mechanisms involving the engagement of α2-subunit containing GABAA receptors in the VTA in the attainment of dominance rank. The involvement of α2-subunit containing GABAA receptors in the VTA in the regulation of social competitiveness supports the potential therapeutic relevance of targeting these receptors to ameliorate anxiety-related social dysfunctions.

2018

A formal total synthesis of the marine alkaloid aaptamine

Blaise Valentin Obrist

A new strategy for the synthesis of benzo[de][1,6]naphthyridine derivative 2,3,3a,4,5,6-hexahydroaaptamine, which involves the construction of the isoquinoline ring after elaboration of the quinoline moiety, is described. Since 2,3,3a,4,5,6-hexahydroaaptamine has been previously synthesized as a key intermediate en route to the marine alkaloid aaptamine, access to this compound represents a formal total synthesis of the natural product. (c) 2008 Elsevier Ltd. All rights reserved.

2008

Diazepam actions in the VTA enhance social dominance and mitochondrial function in the nucleus accumbens by activation of accumbal dopamine D1 receptors

Nature Publishing Group2018