The Joy Of Norepinephrine

Neurotransmitter Is Key To Effects Of Opiates

By Julia DeBaecke

The focus of decades of work to understand the chemical changes that occur from drug use is taking a new turn toward a molecule called norepinephrine (NE). Previously, another neurotransmitter, the so-called "pleasure molecule" dopamine, has received the most attention. But that is about to change with the recent findings reported in the journal Science.

The neurobiology team at the University of Washington (UW) led by principal investigator Richard Palmiter used mouse experiments to demonstrate that NE–not dopamine–is necessary for the rewarding experience of opiates.

Until now, dopamine had been the overwhelming focus of scientists studying the effects of stimuli like food, sex, and drugs.

To reach their surprising result, the UW team created genetically altered knockout mice that have a particular gene removed or "knocked out," in this case the gene that allows NE to be made in the brain. Because these mice lack NE, any changes in their behavior can be attributed in some way to the neurotransmitter's function.

An experimental model called "conditioned place preference" was used to determine whether the knockout mice found opiates rewarding. In the conditioning phase of the experiment, the mice are placed in a two-room chamber and are given morphine in one room and salt water in another. The researchers then record the amount of time they spend in each room. Mice can learn to associate an experience with the place where it occurred, and will spend more time in a location where they received a pleasurable stimulus. When normal mice are placed in the chamber, they seek and remain in the room where they received morphine; in other words, they demonstrate a conditioned place preference. Remarkably, when the NE knockout mice are put in the chamber, they don't show this preference for the morphine-linked area, even when they were given high levels of morphine in that room.

The knockout mice didn't simply have a deficit in learning or attention, since they were able to form a place preference for a room where food was given, and in other studies, cocaine.

Further support for NE's function in reward was provided by injecting the knockout mice with a synthetic compound that is converted to NE in the brain and then performing the same experiment. Once the mice are able to make NE, they behave as normal mice do when placed in the chamber: they were able to experience reward.

So where does this leave dopamine? A graduate student in the Palmiter lab, Thomas Hnasko, investigated dopamine's role in reward using dopamine knockout mice. He found that dopamine is not needed to register pleasure from morphine. The study was published in the December 2005 issue of Nature, and came at nearly the same time as a post-doc in the same group, Valerie Olson, found that the largely ignored NE was actually involved in the rewarding properties of opiates.

The idea that NE might be involved in mediating reward was not new; it was first proposed nearly thirty years ago by Larry Stein, now a pharmacology professor at the Univeristy of California in Irvine. To test his hypothesis, researchers in the 1970s focused on a large region of the brain called the locus coeruleus (LC), which contains most of the brain's NE neurons, to see if NE was important for reward. They were not able to establish a connection between the LC and reward; as a result NE was prematurely dismissed as a candidate for future studies on the reward process. Only recently are neurobiologists discovering that the reason the LC, and therefore NE, wasn't linked to reward all those years ago was that the researchers were looking in the wrong place.

The lead author of the Science report, Olson, discovered not only that NE is needed to register pleasure, but that it acts primarily in a tiny region of the brain called the nucleus tractus solitarius (NTS), not the well-studied LC. "That, I think, was pretty shocking, because most people would have guessed that it was the LC," says Olson.

Olson and her colleagues chose to look into the NTS because there was one study that suggested that the NTS regulates the aversive properties of opiate withdrawal. It was reasonable to hypothesize, Olson says, that "if it can regulate how aversive something is, maybe then it can also affect the positive aspects, or the rewarding aspects of [opiate use]."

In the future, Olson hopes to uncover how neurotransmission from the NTS regulates reward. She also aims to identify the specific receptors involved in the process, which could eventually lead to the development of targeted pharmaceuticals that would short circuit the reward system and be used in the prevention of opiate relapse.

The role of NE in addiction is now coming to the forefront, and researchers are starting to expand their studies beyond dopamine. As a result, a more complete picture of the chemical changes associated with a stimulus such as drug use is emerging.

"If you restrict yourself to only focusing on the dopamine system, then you're missing out. Anybody who studies the brain knows that any disease that you look at, any psychiatric, any neurological illness, is going to have effects on more than just one neurotransmitter system and more than one brain region; it's inevitable because the brain functions as a unit, not just a bunch of independent neurons," says Olson.

Although her study focused on only one neurotransmitter, she keeps her results in perspective: "The holy grail of the one reward circuit, the one brain circuit that activates whenever you're happy is just not going to happen, because we're far more complicated than that."

Julia DeBaecke is a Ph.D. candidate in organic chemistry at the University of Washington.

Image:

A mouse demonstrates a conditioned place preference for the morphine-linked room.