ReviewDrugs, flies, and videotape: the effects of ethanol and cocaine on Drosophila locomotion
Introduction
Drugs of abuse have well-studied effects on locomotion in mammals. In general, low doses stimulate locomotion, whereas higher doses induce repetitive movements called ‘stereotypies’ and/or sedation. Repeated drug administration can lead to the development of behavioral sensitization, which is manifested as an increased response to the drug, or tolerance, which is characterized by a diminished response. Both the stimulant effects of drugs and their ability to induce behavioral sensitization have been proposed to model the positively reinforcing or rewarding properties of the drug 1., 2..
Although not universally accepted, there is significant experimental evidence that supports this hypothesis: at least some of the molecules, neurochemicals and neuroanatomical loci involved in positive reinforcement and reward are also involved in drug-induced locomotor stimulation and behavioral sensitization. For example, it is well known that mesolimbic dopamine systems are involved in drug reinforcement and reward [3]; these systems are also involved in the simpler motor responses induced by acute and repetitive drug administration 4., 5.. It is therefore likely that insights into certain aspects of drug addiction can be obtained by studying these less complex, drug-induced changes in locomotion.
Here we review recent studies that aim to develop D. melanogaster, with its accessibility to genetic, molecular and behavioral analysis, as a model system in which to study the mechanisms underlying drug-induced modulation of locomotor behavior 6., 7..
Section snippets
Effects of ethanol on Drosophila locomotion
Exposing flies to ethanol vapor leads to immediate and marked changes in walking behavior, and several assays have been used recently to document these changes. These include a simple line-crossing assay [8•], an automated beam-breaking assay [9] and a video-tracking system that allows continuous monitoring of locomotion 10•., 11•.. Regardless of the assay used, the general conclusion is that, as in mammals, low doses of ethanol stimulate fly locomotion, whereas high doses depress it.
Role of dopamine in ethanol-induced locomotor stimulation
In the adult fly central nervous system (CNS), dopamine is synthesized by a small number of cells that are scattered throughout the brain and ventral nerve cord (VNC) [15]. Flies in which dopamine synthesis is reduced with the tyrosine hydroxylase inhibitor 3-iodotyrosine (3IY) [16] show a significant impairment in locomotor stimulation induced by ethanol [17•].
Similarly, genetic ablation of neural activity in dopaminergic and serotonergic neurons (using targeted expression of tetanus toxin)
Role of the cAMP pathway in ethanol-induced behaviors
A forward genetic screen for Drosophila mutants with altered ethanol sensitivity carried out by Moore et al. [19] led to the discovery that amnesiac — a gene involved in olfactory learning and memory [20] that encodes a putative neuropeptide thought to activate the cAMP pathway [21] — regulates the effects of ethanol on postural control, as measured in the inebriometer. The inebriometer consists of a 4-foot long vertical column containing a series of sloping mesh baffles on which flies can
Neuroanatomical loci regulating ethanol-induced behaviors
Rodan et al. [10•] have taken an unbiased approach to define regions of the brain and, eventually, the neural circuits where cAMP signaling may regulate ethanol-induced behaviors. By using the GAL4/UAS gene expression system [26], these researchers targeted the expression of a PKA inhibitor to different brain regions using a collection of GAL4 lines with diverse expression patterns in the CNS (see http://www.fly-trap.org/). Of nearly 70 GAL4 lines tested, only 3 showed a specific alteration of
Ethanol tolerance
As shown by Scholz et al. [12•], even a single exposure to ethanol makes flies more resistant to a second challenge applied several hours later. This tolerance is manifested as a delay in ethanol-induced loss of postural control (in the inebriometer), or a delay in sedation (in the locomotor tracking system), and dissipates in about 24 hours. As the kinetics of ethanol accumulation during the first and second exposure are indistinguishable, this tolerance is, by definition, functional and
Cocaine-induced behaviors and the role of dopamine
McClung and Hirsh [36] showed that exposure to free-base cocaine, which is volatilized off a heated filament, induces a range of unusual behaviors in flies: low doses induce continuous grooming; intermediate doses lead to circling and other aberrant walking behavior; and high doses cause fast and uncontrolled movements, and eventually akinesia and even death (Fig. 2). Continuous grooming and circling — behaviors referred to as ‘stereotypies’ — are also observed in rodents on administration of
Cocaine sensitization
As shown by McClung and Hirsh [36], repeated exposure to cocaine makes flies increasingly sensitive to the behavioral effects of the drug. This behavioral sensitization takes time to develop (it is strongest roughly 6 hours after the first exposure) and is long lasting (dissipating about 2 days after a single exposure). The trace amine tyramine, which is synthesized from tyrosine by tyrosine decarboxylase (TDC), has been implicated in cocaine sensitization [44]. Flies carrying the inactive
Circadian rhythms and cocaine sensitization
Repeated cocaine exposure sensitizes not only the behavioral response to cocaine, but also the responsiveness of decapitated flies to application of the dopamine D2 receptor agonist quinpirole to the nerve cord. Andretic et al. [47] showed that these effects are abolished in flies with a mutation in the period gene — one of the central clock genes in Drosophila [48]. Two additional components of the central clock [49], clock and cycle, are also required for cocaine sensitization, which suggests
Conclusions
The behaviors elicited by acute and chronic administration of ethanol and free-base cocaine in flies are remarkably similar, qualitatively and quantitatively, to those seen in mammals. In addition, some reassuring parallels have already emerged at the molecular and neurochemical levels. Although human addiction is an extremely complex condition that obviously cannot be recapitulated in a fruit fly, an understanding of the mechanisms underlying the acute and chronic responses to drugs can be
Acknowledgements
We thank Fred Wolf and Linus Tsai for the data presented in the figures; and Aylin Rodan, Fred Wolf, Doug Guarnieri, Linus Tsai and Bill Cho for helpful discussions and comments on the manuscript. A Rothenfluh is funded by a fellowship from the Swiss Society for Biomedical Stipends and U Heberlein is funded by the National Institutes on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and The McKnight Foundation.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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