BRAIN POWER / MEMORY RESEARCH COULD HELP ADDICTS AND STROKE
VICTIMS

RESEARCHERS ARE closing in on a brain system that seems to be
involved in how memories of pain and pleasure are stored and recalled,
and which offers exciting possibilities for the treatment of
conditions from addiction to head injury and stroke.

It's a highly complex system, as befits a function so important to
survival. After all, if we didn't remember experiences that we liked
(which in most cases are good for us, like eating and reproduction),
we couldn't repeat them and wouldn't last very long as a species. And
if we didn't remember and avoid danger, again, survival would be unlikely.

The story starts in the hippocampus, an area of the brain that gets
its name from the Latin word for seahorse, which describes its shape.
Scientists have long known that this area is crucial to memory and
that damage to it can leave someone in a sort of "infinite present."

Recently, research has begun to yield clues as to how the hippocampus
and other memory areas work. At least two opposing systems of
neurotransmitters seem to be involved - excitatory amino acids such
as glutamate and aspartate, and inhibitory neurotransmitters such as
GABA. The excitatory transmitters make nerves more active; the
inhibitory ones calm them.

"The brain is the most complex machine in the known universe," says
Dr. Michael Rogawski of the National Institutes on Health. "Most nerve
cells use either glutamate or GABA as a transmitter," he explains, and
adds that a function as complicated as memory is bound to involve
numerous nuances.

This much is known: Enhance excitatory amino acid transmission
moderately and you improve memory and recall; enhance inhibitory
transmission slightly and you make memory worse. At the extremes,
both are dangerous - drugs that enhance GABA transmission such as
the so-called date-rape drug Rohypnol (or lots of alcohol) can
eliminate a person's memory of an evening. Overdo it with excitatory
amino acid transmission and you actually kill brain cells - one of
the processes that is believed to cause much of the damage seen in
head injury and stroke.

In the hippocampus, research has found that the neurotransmitter
system that uses excitatory amino acids such as glutamate changes
after certain stimuli. Though the exact process is still unclear, it
seems that receptor changes take place, making it likely that when a
neuron fires simultaneously with another neuron, their connection to a
third neuron will be enhanced. Neuroscientists say, "Those that fire
together, wire together," and this has long been believed to be one
way that memory is stored. Recent work on rats has shown that when
they learn to fear certain stimuli, these changes are visible in their
brains and the rats don't learn to fear the stimuli if one type of
glutamate receptor, called the NMDA receptor, is blocked.

"Thinking broadly, the NMDA receptor is involved in neural plasticity
- - the ability for the brain to change in response to stimuli,
learning, memory and brain development," says Dr. Keith Trujillo,
associate professor of psychology at California State University,
whose research may be seen as one of the foundations of a major
development in addiction treatment.

His work, and that of others, implicates this system in memory of the
drug experience, which is believed to be crucial to causing relapse in
addiction. Studies with drugs that prevent glutamate action at the
NMDA receptor find that at least in rats and mice, these drugs can
prevent the development of tolerance to opiates such as heroin and
can even reverse tolerance that has already developed.

This could be groundbreaking if it holds up in human tests. It would
mean that heroin addiction could potentially be prevented and could
make withdrawal far less punishing. It could also be a major advance
in pain treatment: By administering NMDA receptor-blockers to people
receiving opiates for pain, physicians could prevent the cycle that
leads to a need for increasing doses and results in withdrawal when
the drug is stopped.

Dr. Barbara Herman, health scientist administrator at the National
Institute on Drug Abuse's Medications Development Program, or as she
jokingly called herself, "glutamate girl," said, "I came to NIDA in
1992 and I walked around the Society for Neuroscience meeting, looking
for the hottest thing in medications for addiction. I saw a poster by
Keith Trujillo and Huda Akil, which said that an NMDA receptor
antagonist could inhibit opiate tolerance in rats. I could not
believe that any non-opiate medication could block a process so
strikingly tenacious as tolerance. It is incredibly interesting and it
has caused us to dig deeper to find the best medications with the
fewest side effects."

NMDA receptor antagonists could even potentially be useful in fighting
cocaine and amphetamine addiction, because they prevent one of the
physiological processes which is believed to be important in the
recall of cocaine-related pleasure and which may trigger relapse. Dr.
Peter Kalivas, a researcher at the Department of Physiology and
Neuroscience at the Medical University of South Carolina, said, "It's
possible that if you take one of these drugs when you took cocaine,
you wouldn't develop addiction."

Interestingly, two drugs that block this receptor are already well
known on the street: PCP and ketamine. Because these drugs can cause
serious psychotic reactions, they are not likely to be used in the
treatment of addiction. But another drug in this class is currently
sold over-the-counter in cough medicine. Called dextromethorphan, it
is being tested by the National Institute on Drug Abuse as an aid to
methadone withdrawal. A preliminary safety trial reported no
problematic side effects, according to Herman.

Another small, uncontrolled trial conducted on six heroin addicts by
Dr. Adam Bisaga, a research psychiatrist at Columbia University,
found that dextromethorphan significantly decreased withdrawal
symptoms and craving for drugs. Starting in January, in New York,
Bisaga will be conducting a larger, controlled trial of
dextromethorphan for opiate addiction treatment. "We have to be very
careful that it is safe," says Bisaga, when asked about the potential
for PCP-like side effects. "But it is very promising and we are really
very excited about it."

Another potential drawback to these medications is overall memory
impairments - if a drug makes you forget why you liked cocaine, it
might also make you forget why you liked your boyfriend.

Says Herman, "That will be the $64,000 question. How do these effects
generalize to other learning and memory? If they generalize too much,
the drug would be useless." Herman adds that research is already
finding so much complexity in this receptor system that it will
probably be possible to develop precision drugs to avoid this problem.

And, Kalivas believes that the memory effects disrupt only memories
that would have been formed during the time when you are taking an
NDMA receptor blocker, but he says, even "two hours of no learned
associations" might be dangerous. Plenty can happen in that time -
and being unable to learn and remember it could make someone very vulnerable.

Kalivas is working with experimental drugs that block a glutamate
receptor called the AMPA receptor. He's found that in rats, this drug
can prevent stimuli that normally remind them of cocaine from making
them press a lever to try to get some. This could lead to a drug to
fight cocaine craving - one of the most soughtafter drugs in
addiction treatment. And, Kalivas says, his tests show that the drug
doesn't block stimuli that induce food craving, so it probably
wouldn't generalize and block normal learning.

Glutamate receptor antagonists also seem to have great potential for
combating stroke and head injury. Scientists now believe that most of
the damage that occurs to the brain in both of these types of injuries
(and possibly in Alzheimer's, some severe seizures and cocaine
overdose) results from excessive glutamate release by dying cells,
which, in turn, kills other cells. By blocking glutamate receptors,
this damage may be preventable and people may be able to recover a
much higher level of functioning than was previously thought possible.
NMDA receptor antagonists such as dextromethorphan have so far proved
disappointing in human studies, but other glutamate receptor blockers
may yet work.

Interestingly, a recently discovered synthetic compound derived from
marijuana acts on glutamate receptors and seems to be helpful in
stroke and head injury treatment (and potentially addiction care) as
well.

Checked-by: derek rea