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Targeting the-Dopaminergic Nervous System: Altering Behavior in Larval Zebrafish
Kelly, P., T. Irons, D. L. Hunter, R. C. MACPHAIL, AND S. J. PADILLA. Targeting the-Dopaminergic Nervous System: Altering Behavior in Larval Zebrafish. Presented at Biomedical Research Conference for Minority Students, Charlotte, NC, November 10 - 13, 2010.
This test can be used in future studies to determine the toxic potential of environmental chemicals that are suspected to target the dopaminergic nervous system.
Zebrafish (Dania rerio) are becoming an important model system in studying the effects of environmental chemicals on behavior. In order to develop a rapid in vivo screen to prioritize toxic chemicals, we have begun assessing the acute locomotor effects of drugs that act on the dopaminergic nervous system. In the current study, SKF-38393 [1phenyl- 2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol], a dopamine receptor-1 agonist, was evaluated. In accordance with studies in mammals, this compound was expected to increase locomotor activity in zebrafish. In order to characterize the acute effects of this drug, embryos were reared in 96-well microtiter plates (one embryo per well) until 6 days post-fertilization (dpf). At this age, the larvae are able to swim and respond to stimuli. The embryos/larvae were kept at 26°C in a 14:10 (Iight:dark) cycle, with the light coming on at 0830 hr daily. On day 6, the larvae were administered a range of nonlethal doses (0.1-50 uM) of SKF-38393 by immersion. Each microtiter plate contained control larvae as well as all doses of SKF-38393 (n=12 larvae per dose per plate). Locomotor activity was measured using a Noldus video activity monitor with Ethovision 3.1 software to track the behavior of each individual larval zebrafish under alternating visible light ("light") and infrared light ("dark"). First, a preliminary experiment was conducted in order to determine the time of peak effect for this drug in zebrafish. This time was determined to be 2 hours and 20 minutes after dosing. In the second study, a separate group of larvae were administered the same doses of SKF-38393, and after 2 hours and 20 minutes (time peak of effect), locomotor activity was assessed for 70 minutes. SKF-38393 was found to affect locomotor activity in a dose-dependent manner in 6-dpf zebrafish. As the dose increased, there was an increase in distance moved (1.8 uM and above). These findings are consistent with previous studies in mammals. This test can be used in future studies to determine the toxic potential of environmental chemicals that are suspected to target the dopaminergic nervous system.