Different genes influence toluene- and ethanol-induced locomotor impairment in C. elegans

Davies, Andrew G.; Friedberg, Ryan I.; Gupta, Hersh; Chan, Chung-Lung; Shelton, Keith L.; Bettinger, Jill C.

doi:10.1016/j.drugalcdep.2011.08.030

Cited by 12 publications

(7 citation statements)

References 28 publications

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“…While changes in gene expression following chronic ethanol exposure are well-studied (Mayfield et al, 2008 ), less progress has been made in the examination of those gene changes associated with toluene treatment. In a study with C. elegans , gene expression was differentially altered following chronic exposure to ethanol or toluene (Davies et al, 2012 ). These agents also induced different changes in locomotion with both producing decreased speed, but different patterns of movement (Davies et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

“…In a study with C. elegans , gene expression was differentially altered following chronic exposure to ethanol or toluene (Davies et al, 2012 ). These agents also induced different changes in locomotion with both producing decreased speed, but different patterns of movement (Davies et al, 2012 ). In addition, knock out of slo-1 and rab-3 eliminated the locomotor effects of ethanol, but had no effects on those produced by toluene (Davies et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

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Differential Effects of Toluene and Ethanol on Dopaminergic Neurons of the Ventral Tegmental Area

et al. 2016

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Drugs of abuse increase the activity of dopaminergic neurons of the ventral tegmental area (VTA), and output from the VTA is critical for both natural and drug-induced reward and reinforcement. Ethanol and the abused inhalant toluene both enhance VTA neuronal firing, but the mechanisms of this effect is not fully known. In this study, we used extracellular recordings to compare the actions of toluene and ethanol on DA VTA neurons. Both ethanol and toluene increased the firing rate of DA neurons, although toluene was ~100 times more potent than ethanol. The mixed ion channel blocker quinine (100 μM) blocked the increases in firing produced by ethanol and toluene, indicating some similarity in mechanisms of excitation. A mixture of antagonists of GABA and cholinergic receptors did not prevent toluene-induced or ethanol-induced excitation, and toluene-induced excitation was not altered by co-administration of ethanol, suggesting independent mechanisms of excitation for ethanol and toluene. Concurrent blockade of NMDA, AMPA, and metabotropic glutamate receptors enhanced the excitatory effect of toluene while having no significant effect on ethanol excitation. Nicotine increased firing of DA VTA neurons, and this was blocked by the nicotinic antagonist mecamylamine (1 μM). Mecamylamine did not alter ethanol or toluene excitation of firing but the muscarinic antagonist atropine (5 μM) or a combination of GABA antagonists (bicuculline and CGP35348, 10 μM each) reduced toluene-induced excitation without affecting ethanol excitation. The Ih current blocker ZD7288 abolished the excitatory effect of toluene but unlike the block of ethanol excitation, the effect of ZD7288 was not reversed by the GIRK channel blocker barium, but was reversed by GABA antagonists. These results demonstrate that the excitatory effects of ethanol and toluene have some similarity, such as block by quinine and ZD7288, but also indicate that there are important differences between these two drugs in their modulation by glutamatergic, cholinergic, and GABAergic receptors. These findings provide important information regarding the actions of abused inhalants on central reward pathways, and suggest that regulation of the activation of central dopamine pathways by ethanol and toluene partially overlap.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Differential Effects of Toluene and Ethanol on Dopaminergic Neurons of the Ventral Tegmental Area

et al. 2016

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“…Here, we describe an assay that has been used to identify several molecular and environmental mediators of the acute behavioral response to ethanol 8,10,20,24,25 . This method allows the differentiation and simultaneous examination of two different ethanol response behavior phenotypes, initial sensitivity and the development of acute functional tolerance, that together model the composite phenotype of level of response in mammals.…”

Section: Discussionmentioning

confidence: 99%

“…This assay has been used extensively to study the genetic and environmental influences on the LR to ethanol 8,10,20,24,25 . The mammalian LR phenotype is a composite of at least two components, initial sensitivity to ethanol and acute functional tolerance to ethanol 26,27 .…”

Section: Introductionmentioning

confidence: 99%

An Assay for Measuring the Effects of Ethanol on the Locomotion Speed of <em>Caenorhabditis elegans</em>

Davies

Blackwell

Raabe

et al. 2015

JoVE

Self Cite

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Alcohol use disorders are a significant public health concern, for which there are few effective treatment strategies. One difficulty that has delayed the development of more effective treatments is the relative lack of understanding of the molecular underpinnings of the effects of ethanol on behavior. The nematode, Caenorhabditis elegans (C. elegans), provides a useful model in which to generate and test hypotheses about the molecular effects of ethanol. Here, we describe an assay that has been developed and used to examine the roles of particular genes and environmental factors in behavioral responses to ethanol, in which locomotion is the behavioral output. Ethanol dose-dependently causes an acute depression of crawling on an agar surface. The effects are dynamic; animals exposed to a high concentration demonstrate an initial strong depression of crawling, referred to here as initial sensitivity, and then partially recover locomotion speed despite the continued presence of the drug. This ethanol-induced behavioral plasticity is referred to here as the development of acute functional tolerance. This assay has been used to demonstrate that these two phenotypes are distinct and genetically separable. The straightforward locomotion assay described here is suitable for examining the effects of both genetic and environmental manipulations on these acute behavioral responses to ethanol in C. elegans.

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“…There is now clear evidence that inhalants do not simply act via the same mechanisms as ethanol (45), having discrete effects on both the glutamatergic and GABAergic systems; NMDA and GABA A receptors appear to be stand-out targets with recent evidence suggesting changes to these systems in the medial prefrontal cortex may play a critical role. While relatively independent responses to the glutamatergic and GABAergic systems following inhalants have been presented above, it is likely that toluene-induced adaptations to these systems occur concurrently and have a modulatory effect over the mesocorticolimbic dopaminergic system, thus contributing to the addictive properties of inhalants.…”

Section: Discussionmentioning

confidence: 99%

Conventional Concepts and New Perspectives for Understanding the Addictive Properties of Inhalants

Duncan

Lawrence

2013

J Pharmacol Sci

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Abstract. The abuse of inhaled chemical vapors is a growing problem especially among adolescent populations. This is partly driven by the fact that inhaled products are cheap, accessible, and provide a rapid 'high'. In the brain inhalants have multiple effects. They are neurotoxic, targeting primarily white matter pathways, which is believed to underlie the long-term neurological consequences associated with repeated use. Inhalants are also addictive, resulting in adaptive responses in pathways mediating reward and reinforcement. This includes an ability to alter dopaminergic cell firing and result in long-term mesocorticolimbic dopaminergic dysfunction. However, growing evidence suggests that the reinforcing properties of inhalants may also be driven by their ability to affect neurotransmitter systems other than the dopaminergic system. Both glutamatergic and g-aminobutyric acid (GABA)ergic systems are emerging as key targets of inhalants with differential responses observed following either acute or chronic exposures. These responses appear particularly important in circuits which appear vulnerable to inhalants and which can also modulate dopaminergic function such as the corticostriatal pathway. Thus in combination with the effects of inhalants on dopaminergic systems, our increased understanding of the role(s) of glutamatergic and GABAergic systems provide new and exciting targets to consider for intervention strategies to limit inhalant use.

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Different genes influence toluene- and ethanol-induced locomotor impairment in C. elegans

Cited by 12 publications

References 28 publications

Differential Effects of Toluene and Ethanol on Dopaminergic Neurons of the Ventral Tegmental Area

Differential Effects of Toluene and Ethanol on Dopaminergic Neurons of the Ventral Tegmental Area

An Assay for Measuring the Effects of Ethanol on the Locomotion Speed of <em>Caenorhabditis elegans</em>

Conventional Concepts and New Perspectives for Understanding the Addictive Properties of Inhalants

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