Acute effects of drugs on C. elegans movement reveal complex responses and plasticity

Abstract

Many drugs act very rapidly -- they can turn on or off their targets within minutes in a whole animal. What are the acute effects of drug treatment and how does an animal respond to these? We developed a simple assay to measure the acute effects of drugs on C.elegans movement and examined the effects of a range of compounds including neuroactive drugs, toxins, environmental stresses and novel compounds on worm movement over a time period of 3 hours. We find that many treatments show complex acute responses -- a phase of rapid paralysis is followed by one or more recovery phases. The recoveries are not the result of some generic stress response but are specific to the drug e.g. recovery from paralysis due to a neuroactive drug requires neurotransmitter pathways whereas recovery from a metabolic inhibitor requires metabolic changes. Finally, we also find that acute responses can vary greatly across development and that there is extensive and complex natural variation in acute responses. In summary, acute responses are sensitive probes of the ability of biological networks to respond to drug treatment and these responses can reveal the action of unexplored pathways.\n\nAuthor SummaryDrugs are powerful tools that let us switch on or off key pathways in whole animals and watch the effects. Here we set up a simple assay to measure how drugs affect the movement of the simple nematode C.elegans -- crucially, we look how those responses change over time. We find that worms have complex responses to many different drugs -- they go through clear phases of paralysis and recovery. The recovery from the initial effect of any drug is not due to a generic stress response but is specific to the way each drug acts. We find for example that worms can recover from paralysis driven by one neurotransmitter pathway by activating a different neurotransmitter pathway or from paralysis caused by loss of one metabolic pathway by turning on a second one. These complex responses show how the basic genetic networks that are needed for normal behaviour and function can rewire and respond to the effect of many drugs.\n\nImportantly, the responses can vary in many ways -- different aged worms or different individuals can have different responses and capturing how drug responses change over time is critical to dissect this complexity.