title: Tolerance to anesthesia depends on synaptic proteins.
abstract: The hypnotic effects of anesthetics are caused by their interactions with neuronal components vital for proper signaling. An understanding of the adaptive mechanisms that lead to the development of anesthetic tolerance can offer insight into the regulation of neuroexcitability and plasticity that alter behavioral output. Here we use genetic and pharmacological manipulation of Drosophila to investigate the mechanisms of tolerance to benzyl alcohol. The mutants tested were temperature-sensitive paralytics that interfere with neuronal signaling: two mutations in dynamin that affect vesicle recycling, shi (ts1) and shi (ts2), and one that affects the voltage-activated Na(+) channel, para (ts1). We also used N-ethylmaleimide (NEM) to pharmacologically interfere with synaptic function. We found that blocking the generation of action potentials using a temperature-sensitive paralytic mutation does not induce nor prevent the development of functional tolerance to benzyl alcohol, but that disruption of synaptic signaling using mutations in the dynamin gene or by NEM treatment inhibits the induction of tolerance.
authors.affiliation: The Waggoner Center for Alcohol and Addiction Research, Section of Neurobiology, The University of Texas at Austin, 1 University Station C0920, Austin, TX 78712-0248, USA.
authors.forename: Yazan M
authors.initials: YM
authors.lastname: Al-Hasan
authors.forename: Harish R
authors.initials: HR
authors.lastname: Krishnan
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ghezzi
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Prado
authors.forename: Roseanna B
authors.initials: RB
authors.lastname: Robles
authors.forename: Nigel S
authors.initials: NS
authors.lastname: Atkinson
mesh_terms: D000758:Anesthesia / Q000009:adverse effects*; D000776:Anesthesiology / Q000379:methods*; D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D019905:Benzyl Alcohol / Q000494:pharmacology; D004195:Disease Models, Animal; D004331:Drosophila melanogaster; D004361:Drug Tolerance; D004594:Electrophysiology / Q000379:methods; D005033:Ethylmaleimide / Q000494:pharmacology; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D015398:Signal Transduction; D019966:Substance-Related Disorders; D013569:Synapses / Q000378:metabolism; D013572:Synaptic Vesicles / Q000378:metabolism*; D013696:Temperature; D013997:Time Factors
chemical_list: D000777:Anesthetics; D019905:Benzyl Alcohol; D005033:Ethylmaleimide