Homeostatic Cont of Neural Activity: A Drosophila Model for Drug Tolerance and Dependence

Abstract

Drug addiction is a complex condition of compulsive drug use that results in devastating physical and social consequences. Drosophila melanogaster has recently emerged as a valuable genetic model for investigating the mechanisms of addiction. Drug tolerance is a measurable endophenotype of addiction that can be easily generated and detected in animal models. The counter-adaptive theory for drug dependence postulates that the homeostatic adaptations that produce drug tolerance become counter-adaptive after drug clearance, resulting in symptoms of dependence. In flies, a single sedation with ethanol or with an organic solvent anesthetic (benzyl alcohol) induces functional tolerance, an adaptation of the nervous system that reduces the effect of these neural depressants. Here we review the role of the BK channel gene (slo) and genes that encode other synaptic proteins in the process of producing functional tolerance. These proteins are predicted to be part of an orchestrated response that involves specific interactions across a highly complex synaptic protein network. The response of the slo gene to drug exposure and the consequence of induced slo expression fit nicely the tenets of the counter-adaptive theory for drug tolerance and dependence. Induction of slo expression represents an adaptive process that generates tolerance because it enhances neuronal excitability, which counters the sedative effects of the drugs. After drug clearance, however, the increase in slo expression leads to an allostatic withdrawal state that is characterized by an increase in the susceptibility for seizure. Together, these results demonstrate a common origin for development of drug tolerance and withdrawal hyperexcitability in Drosophila.

The Genetics of Alcohol Responses of Invertebrate Model Systems

“…Implicit in the definition is that a history of chronic ethanol consumption induces the tolerance. For the experimentalist, the definition of ethanol tolerance can be simply stated as ethanol-induced ethanol resistance (Ghezzi & Atkinson, 2011).…”

Drosophilalarvae as a model to study physiological alcohol dependence

“…While the neural circuitry of the fly and the mammalian brain do not resemble one another, there is substantial conservation of genes and signaling pathways in neurons. This conservation is sufficiently high that fly genes that modulate neural excitability or that regulate animal behavior have been used to identify their mammalian counterparts where they perform similar functions 1 , 3 , 5 , 8 , 13 , 20 , 24 . Thus, it is likely that alcohol responses that are mechanistically conserved from flies to mammals arise from the conserved cellular effects of alcohol.…”

A DNA element in the slo gene modulates ethanol tolerance

“…It is distinct from metabolic tolerance, which is the product of an increase in the rate of ethanol clearance. The same adaptations that produce functional tolerance have been linked to physiological dependence and the accompanying symptoms of ethanol withdrawal (Ghezzi & Atkinson, 2011; Koob & Le Moal, 2006; Martin, 1968). However, the correlation between the capacity to acquire tolerance and increased drinking behavior is complex, and may depend both on the way tolerance was induced and the way it was measured (Crabbe et al, 2012; Fritz, Grahame, & Boehm, 2013; Matson, Kasten, Boehm, & Grahame, 2014).…”