PUBLICATION
Novel non-stimulants rescue hyperactive phenotype in an adgrl3.1 mutant zebrafish model of ADHD
- Authors
- Sveinsdóttir, H.S., Christensen, C., Þorsteinsson, H., Lavalou, P., Parker, M.O., Shkumatava, A., Norton, W.H.J., Andriambeloson, E., Wagner, S., Karlsson, K.Æ.
- ID
- ZDB-PUB-221120-1
- Date
- 2022
- Source
- Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 48(8): 1155-1163 (Journal)
- Registered Authors
- Karlsson, Karl, Norton, Will, Shkumatava, Alena, Þorsteinsson, Haraldur
- Keywords
- none
- MeSH Terms
-
- Animals
- Atomoxetine Hydrochloride/pharmacology
- Attention Deficit Disorder with Hyperactivity*/drug therapy
- Attention Deficit Disorder with Hyperactivity*/genetics
- Central Nervous System Stimulants*/adverse effects
- Imidazolines*/therapeutic use
- Methylphenidate*/pharmacology
- Methylphenidate*/therapeutic use
- Mice
- Phenotype
- Zebrafish
- PubMed
- 36400921 Full text @ Neuropsychopharmacology
Citation
Sveinsdóttir, H.S., Christensen, C., Þorsteinsson, H., Lavalou, P., Parker, M.O., Shkumatava, A., Norton, W.H.J., Andriambeloson, E., Wagner, S., Karlsson, K.Æ. (2022) Novel non-stimulants rescue hyperactive phenotype in an adgrl3.1 mutant zebrafish model of ADHD. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 48(8):1155-1163.
Abstract
ADHD is a highly prevalent neurodevelopmental disorder. The first-line therapeutic for ADHD, methylphenidate, can cause serious side effects including weight loss, insomnia, and hypertension. Therefore, the development of non-stimulant-based therapeutics has been prioritized. However, many of these also cause other effects, most notably somnolence. Here, we have used a uniquely powerful genetic model and unbiased drug screen to identify novel ADHD non-stimulant therapeutics. We first found that adgrl3.1 null (adgrl3.1-/-) zebrafish larvae showed a robust hyperactive phenotype. Although the hyperactivity was rescued by three ADHD non-stimulant therapeutics, all interfered significantly with sleep. Second, we used wild-type zebrafish larvae to characterize a simple behavioral phenotype generated by atomoxetine and screened the 1200 compound Prestwick Chemical Library® for a matching behavioral profile resulting in 67 hits. These hits were re-assayed in the adgrl3.1-/-. Using the previously identified non-stimulants as a positive control, we identified four compounds that matched the effect of atomoxetine: aceclofenac, amlodipine, doxazosin, and moxonidine. We additionally demonstrated cognitive effects of moxonidine in mice using a T-maze spontaneous alternation task. Moxonidine, has high affinity for imidazoline 1 receptors. We, therefore, assayed a pure imidazoline 1 agonist, LNP599, which generated an effect closely matching other non-stimulant ADHD therapeutics suggesting a role for this receptor system in ADHD. In summary, we introduce a genetic model of ADHD in zebrafish and identify five putative therapeutics. The findings offer a novel tool for understanding the neural circuits of ADHD, suggest a novel mechanism for its etiology, and identify novel therapeutics.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping