A differential role for neuropeptides in acute and chronic adaptive responses to alcohol: behavioural and genetic analysis in Caenorhabditis elegans.
Prolonged alcohol consumption in humans followed by abstinence precipitates a withdrawal syndrome consisting of anxiety, agitation and in severe cases, seizures. Withdrawal is relieved by a low dose of alcohol, a negative reinforcement that contributes to alcohol dependency. This phenomenon of 'withdrawal relief' provides evidence of an ethanol-induced adaptation which resets the balance of signalling in neural circuits. We have used this as a criterion to distinguish between direct and indirect ethanol-induced adaptive behavioural responses in C. elegans with the goal of investigating the genetic basis of ethanol-induced neural plasticity. The paradigm employs a 'food race assay' which tests sensorimotor performance of animals acutely and chronically treated with ethanol. We describe a multifaceted C. elegans 'withdrawal syndrome'. One feature, decrease reversal frequency is not relieved by a low dose of ethanol and most likely results from an indirect adaptation to ethanol caused by inhibition of feeding and a food-deprived behavioural state. However another aspect, an aberrant behaviour consisting of spontaneous deep body bends, did show withdrawal relief and therefore we suggest this is the expression of ethanol-induced plasticity. The potassium channel, slo-1, which is a candidate ethanol effector in C. elegans, is not required for the responses described here. However a mutant deficient in neuropeptides, egl-3, is resistant to withdrawal (although it still exhibits acute responses to ethanol). This dependence on neuropeptides does not involve the NPY-like receptor npr-1, previously implicated in C. elegans ethanol withdrawal. Therefore other neuropeptide pathways mediate this effect. These data resonate with mammalian studies which report involvement of a number of neuropeptides in chronic responses to alcohol including corticotrophin-releasing-factor (CRF), opioids, tachykinins as well as NPY. This suggests an evolutionarily conserved role for neuropeptides in ethanol-induced plasticity and opens the way for a genetic analysis of the effects of alcohol on a simple model system.
Mitchell
Philippa
P
School of Biological Sciences, University of Southampton, Southampton, United Kingdom.
Mould
Richard
R
Dillon
James
J
Glautier
Steven
S
Andrianakis
Ioannis
I
James
Christopher
C
Pugh
Amanda
A
Holden-Dye
Lindy
L
O'Connor
Vincent
V
D000223:Adaptation, Psychological / Q000187:drug effects*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D003213:Conditioning, Psychological / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D005247:Feeding Behavior / Q000187:drug effects; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009479:Neuropeptides / Q000494:pharmacology*; D010641:Phenotype; D011187:Posture; D017476:Receptors, Neuropeptide Y / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D051036:Large-Conductance Calcium-Activated Potassium Channels; C468272:NPR-1 protein, C elegans; D009479:Neuropeptides; D017476:Receptors, Neuropeptide Y; C494845:slo-1 protein, C elegans; D000431:Ethanol
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