Drug abuse is one of the most devastating social and medical problems in our society, yet little is known about the mechanisms by which these drugs regulate behavior. Our laboratory is using the fruit fly Drosophila, with its accessibility to genetic and molecular analysis, to help establish the missing links between genes and drug-induced behaviors.
Flies display many of the behaviors observed in mammals after both acute and chronic exposure to ethanol. Flies display signs of hyperactivity, incoordination, followed by sedation and hypnosis. In addition, flies develop tolerance to ethanol and undergo 'withdrawal-like' symptoms upon ethanol removal. We have developed assays that allow the quantification of these behaviors and have isolated mutants that respond abnormally to ethanol exposure. For example, mutations in the neuropeptide gene amnesiac are overly sensitive to the sedative effects of ethanol when measured in the inebriometer. We are using similar approaches to study the mechanisms that regulate the responses to psychostimulants such as cocaine, nicotine, and phencyclidine.
In addition to defining drug-induced behaviors and their genetic control, we have begun to map the neuroanatomical sites of drug action and their relation to specific behaviors. Integrating the information gained from behavioral, genetic, molecular, and neuroanatomical analyses will help us gain an understanding of drug-induced behaviors in flies and, eventually, in mammals.
Figure 1. Effects of ethanol on Drosophila locomotion (a) Representation of the locomotor velocity of wild-type flies during an exposure to a moderate dose of ethanol (ethanol exposure period is shown by the grey horizontal bar). (b) Computer-generated traces of the locomotor behavior of a group of 20 flies before and during exposure to ethanol vapor. Each panel corresponds to a 10-s time period recorded at the times indicated in (a).
** Reprinted from Current Opinion in Neurobiology, Vol 6, Rothenfluh A. & Heberlein U., Drugs, flies, and videotape: the effects of ethanol and cocaine on Drosophila locomotion, pp. 639-45, Copyright 2003, with permission from Elsevier.
Figure 2. Computer-generated traces of the locomotor behavior of a group of five flies exposed to volatilized free-base cocaine. Each panel corresponds to a 1-min period starting 2 min after the end of the cocaine exposure. (a) Mock exposure; (b) exposure to 100 µg of cocaine; (c) exposure to 200 µg of cocaine.
** Reprinted from Current Opinion in Neurobiology, Vol 6, Rothenfluh A. & Heberlein U., Drugs, flies, and videotape: the effects of ethanol and cocaine on Drosophila locomotion, pp. 639-45, Copyright 2003, with permission from Elsevier.
Flies in the "booze-o-mat".
The "inebriometers".
Flies receiving nicotine.
A cocaine sensitivity assay.
