Novel melatonin MT, receptor agonists as antidepressants: In vivo electrophysiological and behavioural characterization
Bibliographic record
Abstract
Background: Depression is a mental disorder second only to coronary heart disease as a cause of disability in industrialized countries.Most of the current antidepressants work by blocking the reuptake of serotonin (5-HT) and norepinephrine (NE), two monoamines impaired in mood disorders.Unfortunately, they are fully effective in only one third of patients and produce a wide range of adverse effects.Consequently, novel antidepressant targets are under examination.One promising candidate is the melatonergic system.Melatonin, a neurohormone involved in many physiological processes including mood, exerts its effects mainly by acting on two high-affinity G-protein coupled receptors, MT 1 and MT 2 .The selective roles of MT 1 and MT 2 receptors in mood regulation are poorly understood, though recent studies have indicated MT 1 to be mainly responsible in the mood-related effects of melatonin.Here, we investigated the putative effects of MT 1 receptors on mood regulation by employing a novel selective MT 1 receptor ligand.Methods: We investigated the MT 1 receptor selective partial agonist N-(2-{Methyl-[3-(4-phenylbutoxy)phenyl]amino}ethyl)acetamide (UCM871) using in vivo electrophysiological and behavioural paradigms.To determine the mechanism of MT 1 agonism in depression we employed in vivo electrophysiology to study the modulatory effect of acute UCM871 administration on 5-HT and NE neuronal firing and burst activity in the dorsal raphe nucleus (DR) and locus coeruleus (LC), respectively.We studied the effects of UCM871 in the forced swim test (FST) and the open field test (OFT), well-validated behavioural paradigms for depressive and anxiety-related behaviour.Results and discussion: Remarkably, acute intravenous administration of UCM871 showed a bell-curve effect on firing of 5-HT DR neurons, increasing at lower doses and decreasing at higher doses, increased the number of bursts at its peak dose (7 mg/kg, i.v.), and attenuated the response of 5-HT 1A receptors.In NE LC neurons, increasing doses of UCM871 decreased both firing and burst activity in a dose-dependent manner, with, an increase in the response of alpha-2 adrenergic autoreceptors.The dose of UCM871 producing the peak of 5-HT firing (7 mg/kg) also increased the amount of climbing activity in the FST with no effect on immobility.On the other hand, doses of UCM871
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".