Is alcoholism learned? Insights from the fruit fly☆

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Alcohol addiction is a complex, unique human disease. Breaking addiction down into contributing endophenotypes enables its study in a variety of model systems. The Drosophila model system has been most often used to study alcohol sensitivity, tolerance, and physiological dependence. However, none of these endophenotypes can account for the near-permanent quality of the addicted state. It has been recently discussed that addictive drugs may hijack the learning-and-memory machinery to produce persistent behavioral changes. Learning and memory is amenable to experimental study, and provides us with a window into how alcohol affects higher-order mental functions that are likely to contribute compulsive drug use. Here, we review the Drosophila literature that links alcohol-related behaviors to learning and memory.

Highlights

► Alcohol addiction may involve hijacking of the learning-and-memory machinery. ► Higher-order aspects of addiction have recently been modeled in Drosophila. ► The genes involved in learning and memory overlap with alcohol-related genes. ► Economical Drosophila genetics can contribute to higher-order addiction research.

Introduction

Alcoholism is a serious health concern worldwide. In the United States, almost 4% of the population meet the criteria for alcohol addiction, and alcohol-related problems are estimated to cost more than 223 billion dollars per year [1, 2]. Unfortunately, the success rate of treatment is dismal. During the first year of treatment, two-thirds of individuals have bouts of heavy drinking [3], while the best three year average shows ∼25% rate of recidivism [4]. Rational treatment of alcoholism is dependent on a clear understanding of the mechanics of alcohol addiction.

Addiction to alcohol involves changes that are understandable at the single cell level and also changes that are clearly emergent properties of complex networks of many neurons. In the clinical diagnosis of alcohol dependence (a.k.a. alcohol addiction, alcoholism), an individual is expected to exhibit at least three of seven criteria [5]. Two criteria, tolerance and withdrawal symptoms, are clearly rooted in cellular adaptations to ethanol. The five remaining diagnostic attributes include compulsive ethanol consumption, obsessive desire for alcohol, spending too much time pursuing alcohol, neglecting social, recreational, or occupational activities, and continued alcohol use in spite of accumulating negative consequences. These latter five groups are clearly complex changes in behavior and are probably all emergent properties of a dysfunctional nervous system.

Behavioral responses to ethanol are highly conserved. In mammals and invertebrates, ethanol intoxication proceeds from stimulation to incoordination to sedation with increased dose. These can be followed by the appearance of functional-ethanol tolerance and physiological dependence. Ethanol tolerance is inducible ethanol resistance and in humans includes metabolic (pharmacokinetic) tolerance and functional (pharmacodynamic) tolerance. Functional tolerance of the nervous system is the earliest recognized neuronal plasticity change produced by ethanol. The cellular changes underlying functional tolerance have long been thought to overlap with the changes that produce withdrawal symptoms [6]. Symptoms of withdrawal are indicative of physiological dependence [7]. In Drosophila, a form of rapid ethanol tolerance and an ethanol withdrawal hyperexcitability phenotype have both been shown to share a common genetic basis — the involvement of the slo gene, which encodes the BK-type Ca2+-activated K+ channel [8].

The purpose of this review is to recap recent developments that demonstrate that the Drosophila model system and mammals share some of the higher-order ethanol responses that are linked to alcohol addiction. In general, genetic analysis in Drosophila is more advanced than in mammals. However, the primary value of this model system lies in the fact that Drosophila studies are exponentially cheaper and faster than genetic manipulation of mammals. Between Drosophila and mammals there is a strong and meaningful evolutionary concordance among the genes that underlie cellular activities of the nervous system. However, Drosophila and mammals show poor conservation of brain structures and neural circuitry. This suggests that the conservation of ethanol responses between Drosophila and humans arises because ethanol disrupts evolutionarily ancient attributes of neurons that are capable of adaptation.

Section snippets

Alcohol reward learning in the adult fly

It has been proposed that addiction is a type of pathological associative memory that is produced by the over-activation of a reward pathway [9]. The capacity to learn and remember is functionally and mechanistically conserved phenomena in the Animalia. The learning-addiction link in Drosophila is supported by a recent study in adult flies on the rewarding properties of ethanol. In this study (Figure 1), flies were able to form associations between an odor (CS) and an intoxicating level of

Alcohol-adapted larvae show cognitive alcohol dependence

In a recent study [14], we established the third instar larva of Drosophila melanogaster as an animal model for exploring the relationship between small doses of ethanol and associative learning. In this assay, an otherwise attractive odor (CS) is paired with a heat pulse (US) in three training trials over a 30-min period. Untrained larvae will crawl to a spot of odorant in a Petri dish. However, trained animals have learned to be repulsed by the odor and most of them avoid the odorant (Figure 2

Mutations in learning and memory genes disrupt alcohol-related behaviors

Mutation studies have provided further evidence for a linkage between learning and memory genes and addiction. A long list of memory genes have been associated with alcohol sensitivity, functional tolerance, CPP, and drinking in flies (Table 1). One striking recent addition is a mutant allele of the Drosophila discs large 1 (dlg1) gene. The dlg1 gene encodes two proteins — DlgA and DlgS97. The human homolog of DlgA is the PSD-95 synaptic scaffolding protein and the DlgS97 product most closely

Thoughts and conclusions

One particularly vexing aspect of addiction is the persistent nature of the disease. The addicted state persists beyond the period of functional tolerance, physiological dependence, and the manifestation of withdrawal symptoms that are precipitated by abstention. The idea that addictive drugs co-opt the learning-and-memory machinery to produce the long-lasting addictive state is attractive. Addiction has been proposed to represent maladaptive associative learning, in which the drug

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • •• of outstanding interest

Acknowledgements

The authors would like to thank Dr Morikawa and members of the NSA laboratory for valuable insights while writing this manuscript. They also thank Dr Sukant Khurana for assistance with graphical design and Jane Kirschman for copyediting.

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    Funding sources: This work was supported by National Institute of Health Grant R01AA018037 to NSA and T32AA007471 awarded to BGR.

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