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Research
Volume 13, Number 6 (March, 1999)

Compound Enhances Memory in Mice With Alzheimer-like Symptoms

By Steven Stocker, NIDA NOTES Contributing Writer


A compound developed as an offshoot of drug abuse research is proving effective as a memory enhancer in mice with learning impairments similar to those associated with Alzheimer's disease. The compound, developed by Dr. Tsung-Ping Su in NIDA's Intramural Research Program in collaboration with scientists at the New Jersey Institute of Technology in Newark and SRI International in Menlo Park, California, may prove useful for treating Alzheimer's disease and other causes of memory loss.

Dr. Su and his colleagues synthesized the compound, PRE-084, in 1991 to study the function of proteins called sigma receptors. Like all receptors, sigma receptors are cell proteins that serve as targets for the body's chemical messengers, such as neurotransmitters or hormones. Chemical messengers bind to receptors, either stimulating or inhibiting physiological responses within the cells.

Dr. Su played a key role in the initial identification of sigma receptors in 1982. These receptors seem to play an important role in learning and memory and may play a role in drug addiction. As a compound that acts like a chemical messenger, PRE-084 stimulates these receptors, thus helping scientists identify the physiological responses associated with them.

Working with Dr. Tangui Maurice and Dr. Alain Privat at the Institut National de la Santé et de la Recherche Médicale in Montpellier, France, Dr. Su recently tested PRE-084 in an animal model of Alzheimer's disease. In this model, a fragment of a protein found in the brain is heated to change its shape and then inserted into the brains of young mice. Once in the brain, the distorted fragment causes certain proteins to change their shape also, which disrupts brain function and impairs learning ability. A similar process is thought to occur in Alzheimer's disease, although it occurs over the course of decades rather than days, as was the case with Dr. Su's mice.

In the study, the researchers used two animal learning tests, one for short-term memory and the other for long-term memory. In the short-term memory test, the scientists measured the mice's ability to remember where they had just been in a maze. In the test for long-term memory, the researchers gauged whether the mice remembered a mild footshock they had received 24 hours before.

The Alzheimer-type mice did poorly on both tests, indicating that both their short- and long-term memory had been impaired. Alzheimer-type mice that received PRE-084, however, did almost as well on both memory tests as normal mice did. PRE-084 also produced positive results in another potential mouse model of Alzheimer's disease in which one or more defective genes disturbs learning and memory early in life. Likewise, the compound improved learning and memory in mice with learning deficiencies caused by various chemicals.

The common mechanism behind all these types of learning deficits may be a reduced flow of calcium in neurons, says Dr. Su. Calcium is vital to proper neuronal functioning and appears to play a crucial role in learning and memory, although the exact nature of that role remains a mystery. "We are finding that sigma receptors regulate the flow of calcium into and within neurons," he says. "We think that PRE-084 is able to improve learning and memory in mice with learning deficiencies because, by stimulating the sigma receptors, the compound increases calcium levels in the neurons."

"PRE-084 is interesting because it only operates when the learning mechanisms of the brain are disturbed in some way," adds Dr. Su. "It does not enhance memory in normal mice." The compound produces no toxic effects in either Alzheimer-type mice or normal mice, he notes.

In addition to testing PRE-084, the researchers also investigated the effects of three hormones - dehydroepiandrosterone (DHEA) and pregnenolone sulfate, both of which are secreted by the adrenal glands, and the female sex hormone progesterone - on the memory of the Alzheimer-type mice. The scientists found that DHEA and pregnenolone sulfate improved both short-term and long-term memory, just as PRE-084 did. Progesterone, on the other hand, had minimal effects on its own but blocked the memory enhancing-effects of DHEA and pregnenolone sulfate.

Hormones such as DHEA and pregnenolone sulfate may influence people's ability to learn and remember by stimulating sigma receptors just as PRE-084 does in the mouse studies, Dr. Su says. "As we get older and the DHEA levels in our blood go down, the sigma receptors in our brains may not be stimulated as much as when we were younger, which might cause calcium levels within neurons to decrease, and this may be one reason that we start to lose our memory as we age," says Dr. Su.

Dr.

Dr. Tsung-Ping Su in NIDA's Intramural Research Program has helped develop a compound that may prove useful for treating Alzheimer's disease and other causes of memory loss.
The Link to Drug Abuse

Research indicates that, in addition to playing a role in learning, sigma receptors also may be important in the development of drug dependence. NIDA grantee Dr. Yossef Itzhak at the University of Miami School of Medicine in Miami, Florida, has shown that long-term administration of methamphetamine to rats increases the number of sigma receptors in various areas of the brain. Long-term administration of stimulants such as methamphetamine or cocaine also causes rodents to go through a process called sensitization, in which they become increasingly sensitive to the energizing effects of the stimulants until eventually they run around in their cages in a frantic fashion and perform purposeless movements, such as shaking their heads. Scientists think that this behavior may parallel the increasing anxiety and drug craving that humans feel after taking a stimulant repeatedly.

Because methamphetamine is associated with both sensitization and an increase in sigma receptors, it could be that the receptor increases play a role in sensitization, says Dr. Su. "Dr. Itzhak's study is one of the few reports to have demonstrated biochemical changes associated with sensitization," he notes.

Sources

Itzhak, Y. Repeated methamphetamine-treatment alters brain sigma receptors. European Journal of Pharmacology 230(2):243-244, 1993.

Maurice, T.; Roman, F.J.; Su, T.-P.; and Privat, A. Beneficial effects of sigma agonists on the age-related learning impairment in the senescence-accelerated mouse (SAM). Brain Research 733:219-230, 1996.

Maurice, T.; Su, T.-P.; Parish, D.W.; and Privat, A. Prevention of nimodipine-induced impairment of learning by the selective sigma ligand PRE-084. Journal of Neural Transmission 102:1-18, 1995.

Maurice, T.; Su, T.-P.; and Privat, A. Sigma1 (sigma1) receptor agonists and neurosteroids attenuate Beta25-35-amyloid peptide-induced amnesia in mice through a common mechanism. Neuroscience 83(2):413-428, 1998.

Su, T.-P.; Wu, X.-Z.; Cone, D.J.; Shukla, K.; Gund, T.M.; Dodge, A.L.; and Parish, D.W. Sigma compounds derived from phencyclidine: Identification of PRE-084, a new, selective sigma ligand. The Journal of Pharmacology and Experimental Therapeutics 259(2):543-550, 1991.

NIDA NOTES - Volume 13, Number 6

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