Caenorhabditis elegans as a Model to Study the Molecular and Genetic Mechanisms of Drug Addiction

Abstract

Drug addiction takes a massive toll on society. Novel animal models are needed to test new treatments and understand the basic mechanisms underlying addiction. Rodent models have identified the neurocircuitry involved in addictive behavior and indicate that rodents possess some of the same neurobiologic mechanisms that mediate addiction in humans. Recent studies indicate that addiction is mechanistically and phylogenetically ancient and many mechanisms that underlie human addiction are also present in invertebrates. The nematode Caenorhabditis elegans has conserved neurobiologic systems with powerful molecular and genetic tools and a rapid rate of development that enables cost-effective translational discovery. Emerging evidence suggests that C. elegans is an excellent model to identify molecular mechanisms that mediate drug-induced behavior and potential targets for medications development for various addictive compounds. C. elegans emit many behaviors that can be easily quantitated including some that involve interactions with the environment. Ethanol (EtOH) is the best-studied drug-of-abuse in C. elegans and at least 50 different genes/targets have been identified as mediating EtOH’s effects and polymorphisms in some orthologs in humans are associated with alcohol use disorders. C. elegans has also been shown to display dopamine and cholinergic system–dependent attraction to nicotine and demonstrate preference for cues previously associated with nicotine. Cocaine and methamphetamine have been found to produce dopamine-dependent reward-like behaviors in C. elegans. These behavioral tests in combination with genetic/molecular manipulations have led to the identification of dozens of target genes/systems in C. elegans that mediate drug effects. The one target/gene identified as essential for drug-induced behavioral responses across all drugs of abuse was the cat-2 gene coding for tyrosine hydroxylase, which is consistent with the role of dopamine neurotransmission in human addiction. Overall, C. elegans can be used to model aspects of drug addiction and identify systems and molecular mechanisms that mediate drug effects. The findings are surprisingly consistent with analogous findings in higher-level organisms. Further, model refinement is warranted to improve model validity and increase utility for medications development.

Unraveling the Mechanisms of Behaviors Associated With AUDs Using Flies and Worms

“…In the future, Drosophila and C. elegans can be used as screening platforms to test the efficacy of pharmacological compounds to disrupt alcohol‐related behaviors (Koyyada et al., ; Ranson et al., ; Scott et al., ,b). Finally, the use of Drosophila and C. elegans as genetic model organisms can also be extended to study other drugs of abuse, such as nicotine or cocaine (reviewed by Dupuis et al., ; Engleman et al., ; Haydon et al., ; Kaun et al., ; Kudelska et al., ; Lowenstein and Velazquez‐Ulloa, ; Matta et al., ).…”

Crossing the Worm-Brain Barrier by Using <b><i>Caenorhabditis elegans</i></b> to Explore Fundamentals of Human Psychiatric Illness

“…Previous articles have focused on the use of C. elegans to understand learning and memory [6], movement disorders [7], and drug addiction [8]. Little has been written about its utility for learning more about mental illness.…”

Cannabinoids Stimulate the TRP Channel-Dependent Release of Both Serotonin and Dopamine to Modulate Behavior inC. elegans

“…Our recent work has identified many similarities between CB signaling in mammals and nematodes. Indeed, the utility of C. elegans as a translational tool for understanding basic processes and drug action in the mammalian nervous system is well documented (Engleman et al, 2016). Although C. elegans contains a compact nervous system (only 302 neurons and ϳ7000 synapses), it still exhibits complex behaviors modulated by serotonergic, dopaminergic, adrenergic (octopaminergic), and opioid signaling that are mediated by receptors with clear orthology to their mammalian counterparts (Allen et al, 2011;Law et al, 2015;Mills et al, 2016;Oakes et al, 2017).…”