521. L655,708 A NEGATIVE ALLOSTERIC MODULATOR AT OF GABAA RECEPTOR INCREASED DOPAMINE NEURONAL ACTIVITY UP TO 1 WEEK AFTER A SINGLE INJECTION
Notice bibliographique
Résumé
Abstract Background Negative allosteric modulators of gamma-aminobutyric acid A receptors (GABAA-NAMs) bind with high affinity at the α5 subunit located primarily on glutamatergic pyramidal neurons in the prefrontal cortex (PFC) and hippocamps, thereby directly increasing AMPA throughput [2]. Their specificity limits off-target effects, reducing the possibility of adverse side effects. The α5-preferring GABA-NAM L655,708 has been shown to exert rapid and sustained antidepressant-like action in rats subjected to mild stress. Aims & Objectives It is hypothesized that the monoamine system in conjunction with the glutamatergic system, may play a role in the antidepressant effects of L655,708. Method Experiments were performed in male Sprague-Dawley rats anesthetized using chloral hydrate. in vivo electrophysiological recordings of pyramidal and dopaminergic (DA) neurons were carried out in the PFC and ventral tegmental area (VTA), 24 hours after a single administration of vehicle solution or L655,708 (3 mg/kg; i.p.) and 1 week after for the VTA. Neuronal firing was analyzed for changes in spike frequency and burst activity as well as the number of spontaneously active neurons per track in the VTA (population activity). Results A single administration of L655,708 1-day before electrophysiological recordings did not significantly alter pyramidal neuronal activity in the PFC; firing rate (Vehicle: 1.0 ± 0.3 Hz; L655,708 0.9 ± 0.1 Hz), burst rate (Vehicle: 67 ± 4.8; L655,708 62 ± 4.1). However in the VTA, 24 hours following injection of L655,708, there was a robust enhancement in the number of spontaneously active DA neurons compared to vehicle administration, (Vehicle: 1.3 ± 0.1 Hz; L655,708 3.3 ± 0.1 Hz; two-tailed t test t(5)=8, p<0.001). This increase in population activity observed in the VTA 1-day post-treatment was diminished after the administration of flumazenil, a competitive GABAA receptor antagonist, and the administration of NBQX, an AMPA receptor antagonist. Interestingly, 1 week following the injection of L655,708, there was a significant 2-fold enhancement in the number of spontaneously active DA neurons in the VTA compared to vehicle administration (Vehicle: 1.0 ± 0.1 Hz; L655,708 2.4 ± 0.2 Hz; two-tailed t test t(5) =6, p=0.002). Discussion & Conclusions While no changes were observed in the activity of pyramidal neurons in the PFC 24 hours after injection, L655,708 caused a significant increase in the population activity of DA neurons in the VTA 1 day and 1 week after injection. These results align with data showing that this drug produced an antidepressant-like effect in the forced swim test at 1 day and 1-week post-treatment [1]. The reversal of these effects with the administration of flumazenil and NBQX indicates that L-655-708 indeed binds to the benzodiazepine site on GABAA receptors and that the observed response is AMPA receptor-dependent. The increase of DA neuronal activity by L655,708 is unlikely due to an impact of the drug on PFC pyramidal neurons. Concurrently, the increase in DA population activity without the alteration of firing and burst activity may be attributed to an L-655,708 induced increase in ventral hippocampal activation [3].
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,006 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».