"There are human epidemiological data of others indicating that mild [to] moderate drinking may paradoxically improve cognition in people compared to abstention," says Maggie Kalev, a research fellow in molecular medicine and pathology at the University of Auckland in New Zealand and a co-author of an article in The Journal of Neuroscience describing results of a study she and other researchers performed on rats. "This is similar to a glass of wine protecting against heart disease, however the mechanism is different."
Kalev and Matthew During, a professor of molecular virology, immunology and medical genetics at The Ohio State University College of Medicine and a principal investigator of gene therapy at Auckland, initially set out to study the role of N-methyl-D-aspartic acid (NMDA) receptors in the neuronal processes of normal and diseased animals. (NMDA receptors are critical to memory, because they regulate the strength of synapses (spaces) between nerve cells through which the cells communicate.) But during their research, they discovered that memory was enhanced when one of its subunits, known as NR1, was strengthened in the hippocampus (a central brain region implicated in episodic memory). They then reviewed previous experiments, which had turned up a link between alcohol consumption and NR1 activity.
"We decided to study if beneficial effects of low-dose alcohol drinking already shown by others," Kalev says, "could be mediated through the mechanism of increasing NR1 expression. We thought it was worth pursuing, since ethanol drinking is such a common pattern of human behavior."
The researchers created two strains of transgenic rats, one that had an abundance of NR1 subunits in their hippocampi and one in which it was suppressed. A group of normal rats and those with the suppressed NR1 action were fed a diet consisting of 0, 2.5 or 5 percent ethanol.
According to Kalev, it is hard to relate the alcohol the rats consumed to human quantities, but "based on their blood alcohol levels, the 2.5 percent ethanol diet was equivalent to a level of consumption that does not exceed [the] legal driving limit. This may be approximately one to two drinks per day for some people or two to three for others, depending upon their size, metabolism or genetic background."
The rats stayed on these diets for eight weeks; behavioral testing to assess cognitive function began after four weeks. One test involved novel object recognition, where rats were placed in a cage with two small objects inside multiple times over a two-day period. Then, one object was swapped for a new toy and rats were scored based on how quickly they explored the unfamiliar piece. In a second paradigm, rats were trained to expect a shock when they crossed from a white compartment to a black one inside a cage; a day after training, the rats were put back in the cage to see if they remembered that the black side was dangerous.
Among the normal rats, the animals that consumed moderate amounts of alcohol fared better on both tests compared with the teetotalers. Rats on a heavy alcohol diet did not do well on object recognition (and, in fact, showed signs of neurotoxicity), but they performed better than their normal brethren on the emotional memory task.
"People often drink to 'drown sorrows,'" Kalev says. "Our results suggest that this could actually paradoxically promote traumatic memories and lead to further drinking, contributing to the development of alcoholism."
Overstimulating the NR1 subunits of the NMDA receptor showed effects similar to those from moderate drinking, whereas suppressing the NR1 subunits canceled out the effect of low, but steady consumption. These findings indicate that the NMDA receptor must be intact for the positive effects of alcohol to manifest, Kalev says. They speculate that the NMDA receptor is initially blocked by alcohol, causing the activity of the NR1 subunit to elevate as a compensatory response (thereby conferring heightened cognition).
Meir Stampfer, a professor of nutrition and epidemiology at the Harvard School of Public Health in Boston, says that the new work provides a stronger biological basis for studies that he and others have undertaken linking improved memory to moderate alcohol intake. "[This study] provides interesting evidence for a mechanism that may be operating at the NMDA receptor," he says, but quickly cautions: "It's better not to drink at all than to drink too much," as is also demonstrated by this study.