The Why Files The Why Files --

Brain on drugs... The science of drug receptors

Working in unison
We've discussed the cannabinoid and opiate receptor systems as if they were separate, but actually the systems interact in matters of pain, reward and addiction. Photo of men gathered in a crude laboratoryAlthough various drugs initially act through their own receptors, they eventually trigger a generalized reward system in the brain, which can also be triggered by other drugs. In tobacco smokers, for example, nicotine triggers the release of endogenous opioids and dopamine, a molecule that helps neurons communicate.

Seized heroin refinery in Southeast Asia.
Photo: CIA

The genetics of drug receptors affects the human response to drugs, according to recent studies:

Variants in the CB(1) receptor gene "distinguish addicts from non-addicts," says George Uhl, chief of the Molecular Neurobiology Research Branch at the National Institute of Drug Abuse. By "addict," Uhl means people who are dependent on one, or usually several, psychoactive drugs. The issue is debated, but he thinks "most people who are addicted have a preference for a drug, but they are really addicted to drugs. Half of the vulnerability to addictions is genetic, and two-thirds to three-quarters of this is shared across substances."

The structure of the mu opiate receptor gene affects how alcohol addicts respond to naltrexone, a blocker of opiate receptors. Alcoholics with one particular form of the receptor gene had lower relapse rates and a longer delay before returning to the bottle (see "A Functional Polymorphism..." in the bibliography). Oddly, the different forms of the opiate receptor may not affect human vulnerability to opiate addiction, adds Uhl.

Mice without a gene for the mu opiate receptor showed "profound differences in their preference for morphine," Uhl says, "and a striking reduction in their response to alcohol and to stimulants." That could explain why naltrexone helps many alcoholics stay sober, adds Uhl.

What is the origin of these intricate signaling systems that rely on drug-related compounds? We wish we knew. Nature recycles stuff that works, as witnessed by the universal adoption of DNA and RNA as the chemical language of genetics. "Once a communications technique evolves, nature tends to reuse it," observes cell biologist Herbert Schuel of the State University at Buffalo. "Unlike people ... cells have a universal language. They communicate by exchanging electrical and chemical signals. It goes back to bacteria, unicellular protozoa, and all the way up. The central nervous system and peripheral organs use the same signaling molecules as all other cells of the body."

Poppy pod with ooze running down its sideRaw opium oozes from a lanced poppy seed pod. Photo: NIH

The role of pain
In people, a primary job of opiates is regulating pain, but why would evolution use chemicals and receptors to reduce pain rather than simply zero out nerves that carry pain? Because "it's a bad thing not to be able to feel pain," Uhl says. "People with congenital insensitivity to pain bump into things but don't know it until their joints don't work. But if you are in a fight for your life, it is a bad thing to be overwhelmed by pain. The ability to feel pain and to modulate it both appear to be important in evolution."

Endogenous opioids do a lot more than just modulate pain, says addiction expert Jon-Kar Zubeita, an associate professor of psychiatry at the University of Michigan. By email, he noted that opiate receptors and endogenous opioids "seem to have a general effect in helping the organism adapt to the environment. They are involved in modulating stress responses, pain, emotional attachment and affiliative behavior, as well as feeding and reward, in animal models and humans."

The opiate-receptor system must be useful, Zubeita says, because it "appears to be present across most [animal] species, from low-level invertebrates to higher order mammals. They are believed to be extremely old (phylogenetically speaking) molecules."

But the opiate receptors can be tricked by heroin and morphine, which produce an exaggerated response, and they also respond indirectly to cocaine, marijuana, alcohol and nicotine, Zubeita adds. Drugs of abuse, he says, bind so intensely to the receptors that they can "literally take over the natural ability of the organism to respond appropriately to both stress and negative stimuli, including responses to injury (pain), as well as natural rewards, such as food, and interpersonal interactions."

Addiction: add it up!
This information is changing our view of addiction, from a personal failing to a brain and biochemical imperative, Uhl says. Traditionally, addictions have been seen as a matter of free will, "but having these receptors in hand has given us a concrete biological explanation to the starting points for addiction."

Graphic shows receptors ready for dopamine
Dopamine is a "feel-good" neurotransmitter. Released dopamine can bind to dopamine receptors on the membrane of a neighboring neuron. Photo: NIDA

Dopamine, a "reward" neurotransmitter that can be triggered by pleasurable activities like eating and sex, and by drugs ranging from alcohol and nicotine to marijuana and cocaine, is a primary player in addiction. Uhl demonstrated dopamine's power to shape behavior when his lab created a mouse lacking the gene for VMAT2, an essential part of the dopamine system. The newborn mice just die, he told us. "They don't eat, they don't drink, their mother can place them on the nipple, but they are not rewarded by eating or drinking. It's lethal."

In evolutionary terms, he says, nothing is more powerful than something that kills a young animal. And that is one reason to consider a biological explanation for the compulsive drug-seeking behavior of many addicts. "If we talk in a more biologic, less fearful context, we can think of craving as a part of normal biology," Uhl says. "It gives a sense of the power that drugs can exert. If you don't reproduce, your genes are not passed on. Even people who don't have a personal experience of addiction can understand the power of drugs that can hijack a brain mechanism that ensures the survival of the species."

Survive, thrive and read.


Megan Anderson, project assistant; Terry Devitt, editor; S.V. Medaris, designer/illustrator; David Tenenbaum, feature writer; Amy Toburen, content development executive

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