Jilted Drosophila Melanogaster Flies Turn to Alcohol for Consolation-Studies into Addiction
Drosophila Fruit Flies Are Models for Human Biology
In the past few days a number of news stories, suggesting that drosophila flies unlucky in love became alcoholics, caught my eye. The fruit fly, drosophila melanogaster, has been a favourite model system for the study of genetics and developmental biology. It is easy and cheap to care for, has a short life-cycle (7 days from egg to adult in warm temperatures), and the females lay many eggs. In the past 25 years many techniques for producing genetically modified flies, in which the function of genes can be elucidated through either gain-of- or loss-of-function studies have been developed. The relative simplicity of the fly genome, it has only four chromosomes, makes it particularly amenable to genetic studies.
Drosophila Flies Mimic Human Alcoholic Behaviour
Despite being an invertebrate, and only distantly related to mammals, many of the molecules and pathways that regulate the embryonic development in flies are conserved in higher organisms, and much that is learned in flies can be related to understanding human biology in health in disease. In fact fruit flies are used as model organisms for diseases such as Parkinson’s, Huntingdon’s and Alzheimer’s.
However using fruit flies as a model for studying addiction, a quintessentially human behaviour seems strange. Yet over a decade of work on flies has produced a lot of evidence that human addictive behaviour has a strong genetic, biological basis, and that addiction to alcohol can be reproduced in flies. Much of this work was done in the laboratory of Ulrike Heberlein at the University of California San Francisco. She found that flies could develop an addiction to alcohol that in many ways resembled that of humans, flies would be given a choice of normal food, or food laced with 15% alcohol. With time fly ‘alcoholics’ will choose the food mixed with alcohol, even if its taste is unpalatable, will consume more of it with time, and will binge on alcoholic food if they are deprived of it for a time.
Initially the aim was to try to isolate the genes that played a role in resistance to the intoxicating effects of alcohol, since sensitivity to alcohol had been found to correlate with the increased risk of future alcoholism. A very useful method to discover which genes are important for a particular biological process, is to introduce random mutations into fly embryos, then perform a genetic screen, identifying mutants with a phenotype relevant to the process being studied (in this case increased inebriation when given alcohol, or the opposite, increased resistance), and finally to ‘map’ the mutated gene. The study isolated a mutant that was resistant to the sedative effects of alcohol, named happy hour. Drosophila geneticists are particularly fond of giving genes whimsical names, the contrasting mutant, which was particularly sensitive to the effects of alcohol, was called cheap date.
Depriving Flies of Reward Causes Them to Choose Alcohol Due to its Effect of NPR Levels
In the most recent paper they investigated how the molecular pathways controlling the demand for reward are involved in developing addictions. Neural circuits that make animals seek ‘reward’ are hard wired into the brain of flies as well as humans, and are important for behaviours such as feeding, sexual reproduction, and social behaviour (without them we might forget to eat and die of starvation). Drugs co-opt these pathways leading to addiction. The researchers would deprive male flies of ‘reward’ by placing them in a container with an unresponsive female who would refuse to mate. Such flies were far more likely to binge on alcohol-laced food, then flies that were put in containers with responsive females. The behaviour correlated well with the levels of a molecule known as neuropeptide R (NPR) in the flies’ brains, rejected males had low levels of NPR whereas happy, mated flies had high levels. What is more, it was possible to protect flies from the effects of rejection, by genetically manipulating the levels of NPR. Flies that were modified to express high NPR levels constitutively, did not prefer alcoholic food, even if they were rejected by females, thus behaving like the happy males who were not deprived of mating. Conversely genetically engineering low levels of NPR made flies choose alcohol even if they had mated.
The significance for humans is that there is a closely related neuropeptide called NPY in human brains. Low levels of NPY had been associated with depression or post-traumatic stress disorder and it is known to play a role in feeding, anxiety and sleep. In fact NPY is known to play a role inobesity and anorexia nervosa. Now it appears that NPY might also play a role in chemical addiction. This raises the possibility of helping addicts by developing drugs that will act on NPY receptors, although, of course, since human brains are much more complicated than flies, and NPY appears to play a part in many process, such drugs will not become available any time soon.
The research was published in: G. Shohat-Ophir, K. R. Kaun, R. Azanchi, U. Heberlein. Sexual Deprivation Increases Ethanol Intake in Drosophila. Science , 2012; 335 (6074): 1351 DOI: 10.1126/science.1215932