Research Highlight: The Bottom-Up Approach with Diazepam

By Kurtis Chien

Diazepam, originally sold under the brand-name Valium, is a sedative drug used to treat anxiety symptoms (1). Despite the sedative properties, current and past research indicate that diazepam can amplify aggressive behavior (1).

I spoke with Dr. Klaus Miczek, a professor of psychology, pharmacology, and neuroscience. Dr. Miczek’s laboratory researches the relationship between stress and drug abuse, as well as the brain mechanisms involved with aggression.

Dr. Miczek has researched diazepam and similar benzodiazepines in animal models. In his experiments, mice, rats, or monkeys could receive a drug treatment before encountering another animal (2). The drug’s effects on the experimental animal’s behavior toward the intruding animal could then be observed and manipulated with adjustments to the drug dosage (2). “These drugs follow in a very lawful manner, an inverted U-shape dose-effect curve,” Dr. Miczek tells me (2). That is, along the initial segment of the curve, increasing dosage results in a subsequent increase in aggressive behavior (2). As for the latter segment, the higher doses have a sedative effect, sometimes enough to put the animal to sleep (2).

With the drug action in mind, Dr. Miczek and other researchers set out to determine the mechanism of action. By using benzodiazepine receptor antagonists, it was discovered that benzodiazepines change the conformation of the GABAA receptor molecule (2). These receptors are targeted by the inhibitory neurotransmitter GABA, also known as gamma-aminobutyric acid, which allows chloride ions to flow into the cell (2). “Turns out, that benzodiazepines share this action with alcohol,” Dr. Miczek remarks (2). Unsurprisingly, the graph of aggression vs. alcohol resembles the dose-effect curve for aggression vs. diazepam.

GABAA is a receptor molecule with five subunits (2). The α2 subunit is relevant to the regulation of aggression, and it is the subunit that benzodiazepines interact with (2). Now, what is left to be done is to experimentally determine the genes that express these subunits (2). Perhaps, once the genes responsible have been discovered, they can be manipulated so that inactivation of aggression-related receptors can prevent the aggression-heightening effects of alcohol and diazepam (2).

However, to approach aggression in a bottom-up manner would be getting just half of the picture (2). Seeking and manipulating the gene that codes for the α2 subunit on the GABAA receptor cannot account for the complexity of the polygenic phenomenon that mediates aggression (2). A top-down approach would then be to take the domain of aggression and to study the myriad of factors that control it (2). The picture would be complete when the two approaches complement each other (2). “But we’re far from it,” says Dr. Miczek (2). Until then, he notes, “it’s important to remember that aggression is not explained by a single gene” (2).

 

References:

  1. Diazepam. (2005, March 25). Retrieved October 26, 2017, from https://pubchem.ncbi.nlm.nih.gov/compound/diazepam#section=Top
  2. Miczek, K. (2017, October 20). Personal Interview.