Molecular Action of Popular Antianxiety Drugs Probed

Research Seeks to Separate Basis of Benefits from that of Addiction and Other Side Effects

Popular drugs prescribed to ease debilitating anxiety in people and to restore a good night’s sleep gave monkeys a serious case of the munchies, report researchers at the New England Primate Research Center.

The study may help explain the longstanding complaint of weight gain in patients who take the drugs. It also supports experimental evidence of increased food consumption in other animals and primates given the same drugs.

Photo by Kristen Toohey James Rowlett and his colleagues are making progress in separating the therapeutic benefits of antianxiety drugs from their side effects by experiments that target various versions of a key neurotransmitter receptor.

The paper in the June 17 Psychopharmacology is the latest morsel from a program designed to unscramble the therapeutic benefits from the unwanted side effects of the benzodiazepines and other drugs that act on the same receptor. These agents include the antianxiety benzodiazepines, such as diazepam (Valium) and alprazolam (Xanax) and a chemically distinct class of drugs that work through the same neurotransmitter receptor, such as the sleep-inducing zolpidem (Ambien) and zaleplon (Sonata).

“Our main focus is the anxiety-reducing compounds,” said senior author James Rowlett, HMS assistant professor of psychobiology in the Psychiatry Department at Beth Israel Deaconess and the primate center. “We’re trying to understand the receptor mechanisms underlying the drug effects. Different subtypes of the receptor may be responsible for different behavioral effects. It may be possible to separate the therapeutically useful from the unwanted side effects.”

Valium and other benzodiazepines are fast acting and effective antianxiety agents, sedatives, anticonvulsants, and muscle relaxants. Despite these drugs being some of the safest known to psychiatric medicine, Rowlett said, scientists have been trying to come up with drugs that work as well without the side effects ever since the “Valium scare” of 1979. By then, diazepam had become the most widely prescribed drug in the United States and Europe. But accounts of abuse and dependence—as in the Rolling Stones’ song referring to “mother’s little helper”—escalated and finally culminated in U.S. Congressional hearings. As a consequence, benzodiazepines are regulated by the U.S. Drug Enforcement Agency and similar agencies worldwide. The restrictions largely limit the length of time a benzodiazepine-type drug can be prescribed.

Another contributing factor to the benzodiazepines’ bad press was an implicit trivialization of anxiety disorders, which were not viewed as a biological illness akin to depression and psychosis, noted Jerrold Rosenbaum, head of the Psychiatry Department at Massachusetts General Hospital, in an article last year in the Journal of Clinical Psychiatry. Now, anxiety disorders are among the most frequently diagnosed in psychiatric medicine worldwide.

Rowlett first became interested in studying benzodiazepines to understand the mechanism behind the abuse. Recent epidemiological data suggest an upswing in abuse of benzodiazepine-type drugs, especially in recreational abuse among younger people, often in combination with alcohol or heroin. He was also interested in the source of unwanted side effects. Daytime sleepiness and muscle coordination problems are usually transient, but the higher risk of falls and hip fractures among the elderly taking the drugs is well documented. And for all who take them therapeutically, relatively short chronic exposure can lead to physical dependence and withdrawal symptoms.

Alpha-protein Puzzle
Benzodiazepines and benzodiazepine-like drugs work by boosting the activity of GABA, the principal inhibitory neurotransmitter. GABA was discovered in the mammalian brain in the 1950s and was first identified as an inhibitory neurotransmitter in lobsters in the mid-1960s by several groups (among them neurobiologist Ed Kravitz and his colleagues David Potter, Steve Kuffler, and others at HMS).

The GABA(A) receptor is a ring of five distinct proteins (usually some combination of alpha, beta, and gamma proteins) set into the nerve cell membrane at the synapse. When GABA nuzzles up between the alpha and beta proteins, the pore opens to let chloride ions flow into the cell. The influx of chloride slows down the firing rate of excitatory neurons.

Benzodiazepines and similar drugs bind partway around the ring, between the alpha and gamma proteins, at a site with no known native function. Scientists have discovered that the benzodiazepine-like drugs appear to exert different effects by binding more strongly or weakly to four of the many different versions of the alpha protein found in the GABA(A) receptors. The sleeping drugs zolpidem and zaleplon, for example, selectively prefer the alpha-1 receptor. The alpha-2 and perhaps alpha-3 receptors may mediate the antianxiety action. And, in contrast to the typical memory impairment, compounds active only at alpha-5 may actually enhance learning and memory.

The Match Game
Rowlett and his colleagues are testing the different drugs in observational studies in monkeys to match each alpha-receptor type with its primary effect. It is largely a process of elimination that depends a lot on the properties of the drugs under study. “Our conclusions tend to be as good as the compounds we study are selective,” Rowlett said.

Last year, he and his co-authors showed for the first time in primates that benzodiazepines appear to reduce anxiety through the alpha-2 and alpha-3 receptor types, and not alpha-1. In the Jan. 18, 2005 Proceedings of the National Academy of Sciences, they also suggest that, unfortunately, these GABA(A) receptor types might also play some role in the addictive effects of Valium-like drugs.

The experiments showed that the muscle relaxant properties may come from alpha-2 and alpha-3, and not alpha-1. In contrast, the alpha-1 GABA(A) receptor type may be critically involved in the sedative and motor coordi-nation effects, according to tests with zolpidem. A new drug, L-838,417, which bound to all the receptor types except alpha-1, lacked
sedative effects.

“Sedation is fine if you want a sleep aid, but not if you are trying to go to work,” Rowlett said.

The current study was led by Angela Duke, a graduate student at the University of Massachusetts, Amherst, where Rowlett has an adjunct appointment. She gave the monkeys a series of doses of either the broad-acting antianxiety benzodiazepines diazepam or alprazolam or the alpha-1–selective benzodiazepine-like sleep agents zolpidem or zaleplon. Then she and her colleagues gave them sucrose pellets and observed their feeding behavior for 10 minutes. All the compounds increased pellet consumption by two to three times the normal amount. Blocking the alpha-1 action of the sleeping drugs prevented the overeating. And an experimental agent only active at alpha-5 did not cause overeating.

The sleeping drug Ambien, also known as a hypnotic, has been in the news lately because of reports of unusual sleep activities, including driving and eating, that leave no waking memory. Although the results suggest that the nighttime binging might involve the alpha-1 GABA(A) receptors, it is “still speculative whether this is related to the phenomenon of hypnotic-induced sleep-related eating disorder,” said Michael Silber, co-director of the Mayo Clinic Sleep Disorder Center and the president-elect of the American Academy of Sleep Medicine, who first reported the disorder with co-authors four years ago.

In collaboration with University of Wisconsin chemist and co-author James Cook, Rowlett is hoping to develop and test an elusive alpha-2–selective agent to learn more about the receptor type’s role in reducing anxiety and in producing side effects. “In the field of GABAergic pharmacology, [Rowlett’s] papers are major splashes, because they are pinning down which GABA(A) receptor subtypes mediate which GABA(A) effects,” said Nancy Ator, director of the behavioral biology division at Johns Hopkins School of Medicine. Ator’s nonhuman primate and rodent studies have implicated the alpha-1 receptor in abuse and addiction.

“The thing we know the least about is what we started with—the abuse potential,” Rowlett said. “We don’t have firm evidence that it involves one receptor over another. The only thing we know is that you don’t have to have alpha-1 to have abuse potential, but having alpha-1 activity may make the abuse potential worse.” Rowlett holds out hope that the anxiety-reducing and abuse effects may work through slightly different alpha-receptor types.

—Carol Cruzan Morton

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