Chronic alcohol consumption triggers a host of physiological adaptations in the nervous system. These changes are thought to contribute to learning and memory defects seen in addicts undergoing withdrawal. Such cognitive ethanol dependence has been documented in humans and other vertebrates but never in invertebrates. In a recent edition of Current Biology, Brooks Robinson, Sukant Khurana, Anna Kuperman and Nigel Atkinson, from the University of Texas at Austin, USA, set out to test whether fruit fly larvae undergoing withdrawal from chronic alcohol consumption also have difficulties learning.

The team first tested how acute ethanol consumption affects a larva's ability to learn. Larvae fed ethanol-containing food for 1 h had internal ethanol concentrations equivalent to mildly intoxicating (~0.05 g 100 ml−1) levels in humans. Despite their ‘drunkenness’, these acutely treated larvae were able to navigate away from a noxious stimulus (heat pulse) and towards an attractive odor equally well as animals fed non-alcoholic food. Next, the team paired the unpleasant heat pulse with the attractive odor in training trials, and then assayed whether or not animals would then find the odor repulsive. Animals that were not exposed to ethanol learned to navigate away from the odor after heat pulse training. However, ethanol-fed and heat pulse-trained animals were less likely to navigate away from the odor after training. These results show that acute alcohol consumption impairs a larva's ability to learn to associate noxious heat with odor, but does not affect the animal's ability to sense odor or heat.

Robinson and colleagues next tested associative learning in larvae chronically exposed to ethanol. Surprisingly, after a 6 day binge on food containing ethanol, larvae learned to associate heat pulses with odors just as well as animals that had never been exposed to ethanol. However, after experiencing a 6 h ethanol withdrawal, chronically exposed larvae showed impaired learning. Putting these animals back for 1 h on food spiked with ethanol restored their learning capabilities. These results suggest that larvae can indeed become physiologically adapted to, and cognitively dependent on ethanol.

Increased probability of firing action potentials (i.e. neuronal hyper-excitability) is common in vertebrates undergoing severe ethanol withdrawal. To test for this possibility, Robinson and colleagues fed larvae undergoing withdrawal and tee-total larvae picrotoxin, a drug that induces seizures and hyper-acitivity in excitatory circuits by blocking inhibitory synapses. After a brief picrotoxin treatment, ethanol-adapted larvae going cold turkey showed more seizure-like behavior than similarly treated tee-totallers. This experiment suggests that the central nervous systems of ethanol-adapted larvae are indeed hyper-excited and thus more easily prone to seizures. Furthermore, giving these withdrawing larvae a ‘fix’ (1 h of 5% ethanol in their food) partially reduced their sensitivity to picrotoxin. As ethanol reinstatement rescues both hyper-excitability and learning defects in animals undergoing withdrawal, it is likely that the two effects have related origins. This research therefore strongly suggests that neuronal hyper-excitability contributes in some way to the learning defects in larvae going though ethanol withdrawal.

Overall, the work of Robinson and Colleagues reinforces how eerily conserved ethanol's physiological effects are across animal taxa. Alcohol addiction is truly the great leveller. It doesn't matter whether you are man, mouse or maggot – over-consumption of alcohol will trigger very similar cellular and behavioral responses, with devastating consequences. But we should take heart at this, because it means that we can deploy a wide variety of animal models to effectively study and ultimately combat alcohol addiction.

B. G.
N. S.
Neural adaptation leads to cognitive ethanol dependence
Curr. Biol.