Increased dopaminergic neurotransmission results in ethanol dependent sedative behaviors in Caenorhabditis elegans.

Liliane Schoofs,Pratima Pandey,Kavita Babu,Anuradha Singh,Anindya Ghosh-Roy,Harjot Kaur

doi:10.1371/journal.pgen.1009346

Abstract

Ethanol is a widely used drug, excessive consumption of which could lead to medical conditions with diverse symptoms. Ethanol abuse causes dysfunction of memory, attention, speech and locomotion across species. Dopamine signaling plays an essential role in ethanol dependent behaviors in animals ranging from C. elegans to humans. We devised an ethanol dependent assay in which mutants in the dopamine autoreceptor, dop-2, displayed a unique sedative locomotory behavior causing the animals to move in circles while dragging the posterior half of their body. Here, we identify the posterior dopaminergic sensory neuron as being essential to modulate this behavior. We further demonstrate that in dop-2 mutants, ethanol exposure increases dopamine secretion and functions in a DVA interneuron dependent manner. DVA releases the neuropeptide NLP-12 that is known to function through cholinergic motor neurons and affect movement. Thus, DOP-2 modulates dopamine levels at the synapse and regulates alcohol induced movement through NLP-12.

Highlights

Alcohol is an available drug of abuse used around the world
Our initial analyses indicate that DOP-2 functions in the posterior PDE dopaminergic neuron to allow for normal locomotion in ethanol
We have unearthed the mechanism of DOP-2 functioning and demonstrate that mutants in the dop-2 autoreceptor show increased dopamine release, which in turn causes increased signaling from the neuron postsynaptic to the dopaminergic neuron PDE

Summary

Introduction

Alcohol is an available drug of abuse used around the world. Since excessive alcohol intake is detrimental to human health, many studies have focused on understanding the mode of action and dependency of this drug. Behavioral responses to alcohol and susceptibility to alcohol use disorders (AUDs) vary since they are dependent upon environmental, physiological and genetic differences amongst individuals [1,2]. It is still unclear how alcohol functions to modulate various behaviors, making it important to identify and analyze target gene/s and molecular pathways which functions to modulate behavioral phenotype/s upon alcohol intake. The DA pathway is signals through two types of DA receptors, characterized as D1-like (excitatory) and D2-like (inhibitory) receptors based on their functions and sequence homology (reviewed in [7]). Studies have shown that D2 receptor levels are enhanced in alcoholics and that attenuation in the ligand activation of D2 receptors drives craving and relapse of alcoholism [19,20]

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