Rats depleted of salt become sensitized to amphetamine, show unusual growth of brain cells

Laboratory rats that have been repeatedly depleted of salt become sensitized to amphetamine, exhibiting an exaggerated hyperactive response to the drug and an unusual pattern of neuronal growth in a part of their brains, neuroscientists have found.

The researchers, headed by University of Washington psychologist Ilene Bernstein, discovered that nerve cells in the nucleus accumbens of sensitized rats have more branches and were 30 percent to 35 percent longer than normal. The nucleus accumbens, located in the forebrain, is involved in the reward and motivation system in rats and in humans. It is associated with regulating motivated behaviors of such natural drives as those for food and salt, and for artificial rewards provided by drugs.

The findings are published in the current issue of the Journal of Neuroscience.

“This number, 30 to 35 percent, is startling and implies an ability for neurons to make more connections,” said Bernstein.

The research was triggered by several recent papers. One reported that rats sensitized to amphetamine showed this type of neuron growth. A second found that rats deprived of food seemed to be amphetamine sensitized. When an animal or person becomes sensitized their behavior changes. With amphetamine, animals and people become hyperactive. Rats that are salt sensitized drink and eat salt more rapidly and in greater quantities. Why they behave this way is unknown, Bernstein said.

“That research and ours seem to indicate that being hungry or sodium deprived enough can change an animal’s or a person’s response to a drug even if they have not been exposed to the drug previously,” she said.

“We don’t know if this holds up in humans. But the same part of the brain and the response to drugs holds up across species. The same systems are involved in rats and humans when it comes to amphetamines and cocaine. This suggests evidence of a common natural substrate to natural and artificial rewards that is worth further investigation.”

She added that the findings also point to questions that need to be explored. These include determining how long cross sensitization persists and whether physical challenges such as salt depletion alter people’s responses to drugs.

“There is differential response among people who are challenged or stressed based on their history. Some people may have a life-long susceptibility to these kinds of things. We also need to know why these drugs are so powerful and what systems they are taking advantage of that didn’t evolve naturally.”

In the study, the researchers first gave a group of rats diuretics to deplete them of salt. Then they gave the animals a 3 percent saltwater solution, a mixture they ordinarily would not like or drink. This procedure was repeated two more times, with each treatment given a week apart.

Then the animals’ brains were examined under a microscope, revealing the 30 percent to 35 percent increase in neuron growth in the nucleus accumbens compared to the brains of normal rats. The ends of brain cells, or dendrites, are where neurons make connections with other neurons, implying an ability to make more connections, said Bernstein.

To check for cross sensitization to amphetamine, another group of rats was salt depleted twice. Then they were allowed to explore an open, dark plastic enclosure with the floor divided into a grid by white tape. A week after the second salt depletion, the rats and a control group of animals were injected with amphetamine and placed in the enclosure.

The psychostimulant effects of the drugs were measured by two behaviors – the number of taped lines each animal crossed over and how many times it reared up on its hind feet. The two groups didn’t differ in the number of lines each crossed, but the salt-depleted rats showed significantly more rearing behavior.

What was particularly striking about the findings is that they occurred relatively quickly, just two weeks after the first salt-depletion treatment, said Bernstein.

Other members of the research team included Mitchell Roitman, a UW graduate who is now a post-doctoral researcher at the University of North Carolina, and Theresa Jones, an assistant psychology professor at the University of Texas. The UW’s Royalty Research Fund supported the research.

For more information, contact Bernstein at (206) 543-4527 or ileneb@u.washington.edu