Oregon Health & Science University mouse studies showing prenatal exposure to methamphetamine negatively affects learning and memory are spurring clinical research examining the drug's effects on cognition in children.

Jacob Raber, Ph.D., associate professor of behavioral neuroscience and neurology in the OHSU School of Medicine, is leading the study that will be the first to examine the potential roles that genetics, gender and age play in later-life cognition in children exposed to meth before birth.

"We know that meth is used a lot, especially in Oregon, and many people who use it are of child-bearing age. We know very little about what happens, later in life, to the developing brain when it's exposed to meth during pregnancy," said Raber, an investigator with the Methamphetamine Abuse Research Center (MARC) at Oregon Health & Science University.

"What we've found is that mice exposed to meth early in life show impairment in object recognition, and spatial learning and memory. And female mice are more susceptible than male mice to meth exposure early in life. So we want to see if this is also happening in humans."

Raber's team will examine whether negative cognitive effects of meth are more pronounced in children who carry a member of a series of brain proteins called Apolipoprotein E, or apoE, that are implicated in development, nerve cell regeneration and neuroprotection. The group also will study whether there are differences in learning and memory between apoE-carrying girls and boys

"The other thing we are very interested in is the apoE gene. We want to see if there is a subset of children that is more susceptible (to cognitive changes) because they have a particular genetic factor. Does the genetic factor predispose children to impairment?" Raber asked.

Specifically, the team will study a member of the apoE gene family known as apoE4, which has been shown to increase the risk of cognitive impairments following environmental challenges and to develop Alzheimer's disease, particularly in females. Earlier studies on female mice expressing the human apoE4 gene in their brains developed progressive, age-dependent impairments in spatial learning and memory.

ApoE4 is a risk factor for Alzheimer's disease and might also predispose the brain to the effects of methamphetamine on learning and memory, Raber noted

Researchers also hope the study teaches them more about the role that histamine, a compound released naturally in the brain, plays in the long-term cognitive effects of meth use. In a mouse study published last year, Raber's team found that increasing the release of histamine in the brain mimicked meth's effects, including impairments in object recognition and spatial learning, and memory, while inhibiting histamine blocked these effects.

The results indicate that the histamine system may be an important link to developing an effective target for drug therapies.

"We think histamine plays a major role in mediating these effects," Raber said.

Summer Acevedo, Ph.D., a postdoctoral fellow in Raber's lab, is recruiting boys and girls ages 7 to 9 who were either exposed to drugs of abuse, primarily meth, at any time during more than one month of pregnancy, or not exposed to any drugs, and who are from households with an annual income of less than $35,000 or that qualify for earned income credit or Medicaid. Siblings in this age range also are encouraged to participate in the study, as are children in foster care as long as the biological mother can be interviewed.

"The reason we picked 7- to 9-year-olds is we wanted to get children as young as possible, but they have to be old enough to perform the tasks," Raber said. "It is really a narrow age range, but there are many reasons to try to narrow it down to see if we can see a real effect of meth, and so it's not tainted by puberty."

The study will involve three paper-based tests and three computer-based tests, including a 3-dimensional, computer-generated virtual reality program called Memory Island that assesses spatial learning and memory. Participants, immersed in the simulated world are trained to navigate to a target location marked with a flag, adjacent to the target in each of four quadrants. The participants are given several tries to navigate back to the targets based on memory.

The idea is to mimic the Morris water maze, a commonly used scientific tool for testing memory in rodents by training them to swim to a platform based on visual cues.

Testing sessions will take two hours. Parking permits or bus fare will be provided to all study participants, and a $50 Toys 'R' Us gift certificate will be offered to those completing the testing and interview.

For more information about the study, call Dr. Acevedo at 503 494-1431 or 503 418-0182.

The human studies are funded by the Oregon Clinical Translational Research Institute, and the animal studies are funded by the MARC.