A larval zebrafish model of bipolar disorder as a screening platform for neuro-therapeutics.
Modelling neurological diseases has proven extraordinarily difficult due to the phenotypic complexity of each disorder. The zebrafish has become a useful model system with which to study abnormal neurological and behavioural activity and holds promise as a model of human disease. While most of the disease modelling using zebrafish has made use of adults, larvae hold tremendous promise for the high-throughput screening of potential therapeutics. The further development of larval disease models will strengthen their ability to contribute to the drug screening process. Here we have used zebrafish larvae to model the symptoms of bipolar disorder by treating larvae with sub-convulsive concentrations of the GABA antagonist pentylenetetrazol (PTZ). A number of therapeutics that act on different targets, in addition to those that have been used to treat bipolar disorder, were tested against this model to assess its predictive value. Carbamazepine, valproic acid, baclofen and honokiol, were found to oppose various aspects of the PTZ-induced changes in activity. Lidocaine and haloperidol exacerbated the PTZ-induced activity changes and sulpiride had no effect. By comparing the degree of phenotypic rescue with the mechanism of action of each therapeutic we have shown that the low-concentration PTZ model can produce a number of intermediate phenotypes that model symptoms of bipolar disorder, may be useful in modelling other disease states, and will help predict the efficacy of novel therapeutics.
National Research Council of Canada, Aquatic and Crop Resource Development, 1411 Oxford Street, Halifax, Nova Scotia B3H 3Z1, Canada.
Lee David
LD
Ellis
Kelly Howard
KH
Soanes
D000704:Analysis of Variance; D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D014150:Antipsychotic Agents / Q000009:adverse effects; D001714:Bipolar Disorder / Q000139:chemically induced / Q000188:drug therapy*; D003623:Dark Adaptation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004347:Drug Interactions; D018756:GABA Antagonists / Q000633:toxicity; D006220:Haloperidol / Q000633:toxicity; D007814:Larva; D008012:Lidocaine / Q000633:toxicity; D010433:Pentylenetetrazole / Q000633:toxicity; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D014741:Video Recording; D015027:Zebrafish
D014151:Anti-Anxiety Agents; D014150:Antipsychotic Agents; D018756:GABA Antagonists; D008012:Lidocaine; D006220:Haloperidol; D010433:Pentylenetetrazole