BryLog

Injections of THC, the active principle of cannabis, eliminate dependence on opiates (morphine, heroin) in rats deprived of their mothers at birth. The findings could lead to therapeutic alternatives to existing substitution treatments…. (continues @ ScienceDaily)

A tiny genetic mutation is the key to understanding why nicotine—which binds to brain receptors with such addictive potency—is virtually powerless in muscle cells that are studded with the same type of receptor….

By all rights, nicotine ought to paralyze or even kill us, explains Dennis Dougherty, the George Grant Hoag Professor of Chemistry at Caltech and one of the leaders of the research team. After all, the receptor it binds to in the brain’s neurons—a type of acetylcholine receptor, which also binds the neurotransmitter acetylcholine—is found in large numbers in muscle cells. Were nicotine to bind with those cells, it would cause muscles to contract with such force that the response would likely prove lethal….

The shape of the acetylcholine receptor, and the way the chemicals that bind with it contort themselves to fit into that receptor, is determined by a number of different weak chemical interactions. Perhaps most important is an interaction that Dougherty calls “underappreciated”—the cation-π interaction, in which a positively charged ion and an electron-rich π system come together….

Back in the late 1990s, Dougherty and colleagues had shown that the cation-π interaction is indeed a key part of acetylcholine’s ability to bind to the acetylcholine receptors in muscles. “We assumed that nicotine’s charge would cause it to do the same thing, to have the same sort of strong interaction that acetylcholine has,” says Dougherty. “But we found that it didn’t.”

This would explain why smoking doesn’t paralyze us; if the nicotine can’t get into the muscle’s acetylcholine receptors, it can’t cause the muscles to contract.

But how, then, does nicotine work its addictive magic on the brain?

It took another decade for the scientists to be able to peek at what happens in brain cells’ acetylcholine receptors when nicotine arrives on the scene. Turns out that in brain cells, unlike in muscle cells, nicotine makes the exact same kind of strong cation-π interaction that acetylcholine makes in both brain and muscle cells.

“In addition,” Dougherty notes, “we found that nicotine makes a strong hydrogen bond in the brain’s acetylcholine receptors. This same hydrogen bond, in the receptors in muscle cells, is weak.”

The cause of this difference in binding potency, says Dougherty, is a single point mutation that occurs in the receptor near the key tryptophan amino acid that makes the cation-π interaction. “This one mutation means that, in the brain, nicotine can cozy up to this one particular tryptophan much more closely than it can in muscle cells,” he explains. “And that is what allows the nicotine to make the strong cation-π interaction.”

To summarize, the structure of nicotine-binding acetylcholine receptors in the brain is slightly different from receptors in muscle cells.  This difference causes nicotine to be able to bind to receptors on neurons in the brain, but not onto receptors on muscles.

A precise, new nanotechnology treatment for drug addiction may be on the horizon as the result of research conducted at the University at Buffalo.

Scientists in UB’s Institute for Lasers, Photonics and Biophotonics and UB’s Department of Medicine have developed a stable nanoparticle that delivers short RNA molecules in the brain to “silence” or turn off a gene that plays a critical role in many kinds of drug addiction….

The new approach developed by the UB researchers also may be applicable to treating Parkinson’s disease, cancer and a range of other neurologic and psychiatric disorders, which require certain drugs to be delivered to the brain….

Ok…so what molecule are they targeting?

The PNAS paper describes the development of an innovative way to silence DARPP-32, a brain protein, understood to be a central “trigger” for the cascade of signals that occurs in drug addiction.

DARPP-32 is a protein in the brain that facilitates addictive behaviors. Silencing of the DARPP-32 gene with certain kinds of ribonucleic acid (RNA), called short interfering RNA (siRNA), can inhibit production of this protein and thus, could help prevent drug addiction.

“When you silence this gene, the physical craving for the drug should be reduced,” said Adela C. Boniou, Ph.D., a post-doctoral researcher in the Institute for Lasers, Photonics and Biophotonics in the UB Department of Chemistry in the College of Arts and Sciences, and a co-author.

From someone who is intimately familiar with DARPP-32, this sounds like a horrible idea.  At the most basic level, addiction is not a “natural” state.  Although DARPP-32 may become dysregulated in an addictive state as (animal) models suggest, this protein also has “natural” functions.   Silencing DARPP-32 expression probably will have unintended consequences.  This is especially true for such a complicated molecule as DARPP-32.

Below is a diagram demonstrating such complexities.  DARPP-32 (the blue molecule with either purple or yellow bands) can change it’s role in a cell, either activating or inhibiting other molecules - depending on regulation of DARPP-32 itself by other molecules (such as PKA and cdk5).  Thus, activity and levels the proteins PKA and cdk5 somehow fight each other in brain cells to interact with DARPP-32.  The future actions of DARPP-32 are utterly dependent on this fight.  We really don’t know how this fight occurs in an addicted individual.  In fact, it has been hypothesized that the winner of this fight may influence the reduction of addictive behaviors by DARPP-32.  Therefore, limiting the abilities of DARPP-32, like the researchers in the above study suggest, may infact enhance addiction.

Image from Bibb et al (1999) Nature 402, p669

People are often amazed at the amount of funding for addiction research. They think that addiction is a social disorder alone, and not a physical disease, and thus should require less research attention.  Aside from the fact that drug abuse is a disease and finding of better treatments will reduce governmental treatment costs, the brain systems which drugs of abuse act upon are shared with diseases such as Parkinson’s, Huntington’s, Alzheimer’s, ADHD, and Schizophrenia (to name a few).  Since the effects of an abused drug (such as cocaine) have on the brain are easier to comprehend (in many cases) and control than those of other diseases, abused drugs are useful tools in understanding the shared brain systems.