Fyn Kinase and NR2B-Containing NMDA Receptors Regulate Acute Ethanol Sensitivity But Not Ethanol Intake or Conditioned Reward

Acute exposure to ethanol is known to modulate signalling within the nervous system. Physiologically these effects are both presynaptic and postsynaptic in origin; however, considerably more research has focused primarily on postsynaptic targets. Recent research using the model organism Caenorhabditis elegans has determined a role for specific proteins (Munc18-1 and Rab3) and processes (synaptic vesicle recruitment and fusion) in transducing the presynaptic effects of ethanol. In the present paper, we review these results, identifying the proteins and protein interactions involved in ethanol sensitivity and discuss their links with mammalian studies of alcohol abuse.

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DARPP-32 and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens

Nature Neuroscience ◽

10.1038/nn877 ◽

2002 ◽

Vol 5 (7) ◽

pp. 641-648 ◽

Cited By ~ 112

Author(s):

R. E. Maldve ◽

T. A. Zhang ◽

K. Ferrani-Kile ◽

S. S. Schreiber ◽

M. J. Lippmann ◽

...

Keyword(s):

Nucleus Accumbens ◽

Nmda Receptors ◽

Ethanol Sensitivity

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Ethanol sensitivity of heteromeric NMDA receptors: Effects of subunit assembly, glycine and NMDAR1 Mg2+-insensitive mutants

Neuropharmacology ◽

10.1016/0028-3908(94)00155-l ◽

1995 ◽

Vol 34 (3) ◽

pp. 347-355 ◽

Cited By ~ 109

Author(s):

T. Mirshahi ◽

J.J. Woodward

Keyword(s):

Nmda Receptors ◽

Ethanol Sensitivity ◽

Subunit Assembly

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Conservation of the Ethanol-Induced Locomotor Stimulant Response among Arthropods

Brain Behavior and Evolution ◽

10.1159/000370099 ◽

2015 ◽

Vol 85 (1) ◽

pp. 37-46 ◽

Cited By ~ 3

Author(s):

Christopher L. Kliethermes

Keyword(s):

Drosophila Melanogaster ◽

Behavioral Response ◽

Wolf Spider ◽

Fruit Fly ◽

Vertebrate Species ◽

Ethanol Sensitivity ◽

Locomotor Stimulation ◽

Arthropod Species ◽

Acute Ethanol ◽

Reinforcing Effects

Ethanol-induced locomotor stimulation has been variously described as reflective of the disinhibitory, euphoric, or reinforcing effects of ethanol and is commonly used as an index of acute ethanol sensitivity in rodents. The fruit fly Drosophila melanogaster also shows a locomotor stimulant response to ethanol that is believed to occur via conserved, ethanol-sensitive neurobiological mechanisms, but it is currently unknown whether this response is conserved among arthropod species or is idiosyncratic to D. melanogaster. The current experiments surveyed locomotor responses to ethanol in a phylogenetically diverse panel of insects and other arthropod species. A clear ethanol-induced locomotor stimulant response was seen in 9 of 13 Drosophilidae species tested, in 8 of 10 other species of insects, and in an arachnid (wolf spider) and a myriapod (millipede) species. Given the diverse phylogenies of the species that showed the response, these experiments support the hypothesis that locomotor stimulation is a conserved behavioral response to ethanol among arthropod species. Further comparative studies are needed to determine whether the specific neurobiological mechanisms known to underlie the stimulant response in D. melanogaster are conserved among arthropod and vertebrate species.

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UNC-18 Modulates Ethanol Sensitivity in Caenorhabditis elegans

Molecular Biology of the Cell ◽

10.1091/mbc.e08-07-0689 ◽

2009 ◽

Vol 20 (1) ◽

pp. 43-55 ◽

Cited By ~ 24

Author(s):

Margaret E. Graham ◽

Mark R. Edwards ◽

Lindy Holden-Dye ◽

Alan Morgan ◽

Robert D. Burgoyne ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Point Mutations ◽

Ethanol Exposure ◽

Snare Complex ◽

Motor Dysfunction ◽

Mouse Strains ◽

Ethanol Sensitivity ◽

Ethanol Preference ◽

Protein Receptor ◽

Acute Ethanol

Acute ethanol exposure affects the nervous system as a stimulant at low concentrations and as a depressant at higher concentrations, eventually resulting in motor dysfunction and uncoordination. A recent genetic study of two mouse strains with varying ethanol preference indicated a correlation with a polymorphism (D216N) in the synaptic protein Munc18-1. Munc18-1 functions in exocytosis via a number of discrete interactions with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein syntaxin-1. We report that the mutation affects binding to syntaxin but not through either a closed conformation mode of interaction or through binding to the syntaxin N terminus. The D216N mutant instead has a specific impairment in binding the assembled SNARE complex. Furthermore, the mutation broadens the duration of single exocytotic events. Expression of the orthologous mutation (D214N) in the Caenorhabditis elegans UNC-18 null background generated transgenic rescues with phenotypically similar locomotion to worms rescued with the wild-type protein. Strikingly, D214N worms were strongly resistant to both stimulatory and sedative effects of acute ethanol. Analysis of an alternative Munc18-1 mutation (I133V) supported the link between reduced SNARE complex binding and ethanol resistance. We conclude that ethanol acts, at least partially, at the level of vesicle fusion and that its acute effects are ameliorated by point mutations in UNC-18.

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