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Cocaine is an illegal and addictive drug. It causes addiction by hijacking small molecules called chemical messengers that the cells in the brain use to communicate and work together. Most scientists have studied how cocaine affects three chemical messengers, called serotonin, dopamine, and norepinephrine, but cocaine may also affect a fourth chemical messenger called acetylcholine. To understand whether cocaine affects acetylcholine, we used the egg-laying “brain” of small worms to determine how cocaine works in humans. We found that cocaine makes these worms lay eggs, but only when the acetylcholine message is working properly. This tells us that cocaine acts in part through acetylcholine. Our study provides a first step in understanding the interaction between cocaine and acetylcholine. Treatments for cocaine addiction depend on our understanding of how the drug works, so learning how cocaine affects acetylcholine could lead to the development of effective treatments for cocaine addiction.

Despite the toxicity and addictive liability associated with cocaine abuse, its mode of action is not completely understood, and effective pharmacotherapeutic interventions remain elusive. The cholinergic effects of cocaine on acetylcholine receptors, synthetic enzymes, and degradative enzymes have been the focus of relatively little empirical investigation. Due to its genetic tractability and anatomical simplicity, the egg laying circuit of the hermaphroditic nematode, Caenorhabditis elegans, is a powerful model system to precisely examine the genetic and molecular targets of cocaine in vivo. Here, we report a novel cocaine-induced phenotype in Caenorhabditis elegans, cocaine-stimulated egg laying. In addition, we present the results of an in vivo candidate screen of synthetic enzymes, receptors, degradative enzymes, and downstream components of the intracellular signaling cascades of the main neurotransmitter systems that control Caenorhabditis elegans egg laying. Our results show that cocaine-stimulated egg laying is dependent on acetylcholine synthesis and synaptic release, functional nicotinic acetylcholine receptors, and the Caenorhabditis elegans acetylcholinesterases. Further, we show that cocaine-stimulated egg laying is not dependent on other neurotransmitters besides acetylcholine, including serotonin, dopamine, octopamine, and tyramine. Finally, our data show that cocaine-stimulated egg laying is increased in mutants for the C. elegans serotonin reuptake transporter as well as mutants for a 5-HT-gated chloride channel likely expressed in the locomotion circuit. Together, these results highlight serotonergic inhibition of egg laying behavior, functional connectivity between the egg laying and locomotion circuits in Caenorhabditis elegans, and possible discrete cholinergic and serotonergic effects of cocaine in the egg laying and locomotion circuits, respectively.