Addiction has two components.

Initially, there are the good feelings associated with taking a drug, legal or illegal, which is what gets people addicted in the first place. But once they are hooked, those good feelings tend to diminish over time, a victim of neural adaptation. Oftentimes, what keeps addicts using is the desire to avoid the withdrawal symptoms that come from trying to quit, long after the pleasure effects of a drug are gone with the wind.

The neurotransmitter norepinephrine was a known culprit in the negative symptoms of opiate withdrawal; but whether it is involved in the pleasurable effects of morphine as well has been controversial.

In the Feb. 17, 2006, issue of Science, researchers from the University of Washington in Seattle and New York-based biotechnology company Neurologix Inc. report new research nailing a role for norepinephrine in the rewarding aspects of addiction.

Senior author Richard Palmiter, a professor of biochemistry at the university, referred to the Science paper as a "companion paper" to one published by his laboratory in the Dec. 8, 2005, issue of Nature. In that study, the researchers had shown that dopamine, the most-studied transmitter in addiction research and the usual suspect for any rewarding effects of drugs of abuse, is not involved in at least some of the rewarding effects of morphine.

Together, Palmiter told BioWorld Today, the message of the papers is that "it’s not dopamine, and it is norepinephrine that’s important" for the rewarding effects of morphine.

Norepinephrine is made from dopamine in a single step by the enzyme dopamine beta-hydroxylase or DBH. In the Science article, the researchers used DBH knockout mice in behavioral experiments to determine whether norepinephrine mediates rewarding as well as punishing effects of drugs.

Given that norepinephrine is a major transmitter in the nervous system and the direct precursor for another major transmitter, epinephrine (also known as adrenaline), the knockout animals do surprisingly well - at least after they are born.

"Without intervention, they would all die of cardiovascular failure around embryonic day 10 or 11," Palmiter said. But after birth, norepinephrine is a surprisingly discretionary transmitter to have around. "You would think they would have cardiovascular problems as well," Palmiter said. But the only obvious changes are that they are a bit smaller than wild-type mice and have, of all things, droopy eyelids.

Mice lacking DBH, and consequently, norepinephrine, did not show rewarding effects of morphine injections; but those effects could be restored by giving a pseudosubstrate that restored norepinephrine signaling throughout the brain.

Using gene delivery of the DBH enzyme, Palmiter and his colleagues next selectively restored norepinephrine in two brain regions that are involved in addiction and reward the nucleus tractus solitarius and the locus coeruleus, respectively. Palmiter described the locus coeruleus as "the major source of norepinephrine in the brain; it’s a fairly small nucleus" but has widespread projections, including into the cerebral cortex. The nucleus tractus solitarius is "an even smaller nucleus" that projects to the ventral part of the brain, but not the cortex.

The scientists were able to restore the rewarding effects of morphine by restoring norepinephrine signaling by the nucleus tractus solitarius, but not the locus coeruleus. In contrast, motor effects of morphine were restored when norepinephrine signaling was reinstated in either of the two nuclei.

The experiments address a decades-long controversy about the respective roles of dopamine and norepinephrine in reward. What enabled the researchers to finally develop a clean experimental protocol was the development of DBH-knockout mice and their conditional rescue through gene transfer. "In principle, you could have done it with antagonists, but there are nine norepinephrine receptors" and antagonists usually are given by peripheral injections rather than directly into the brain, Palmiter said. Any findings derived from such an approach probably would have been rather muddled.

In contrast, the behavioral experiments are "simple," Palmiter said. "In fact, If you have a pet, you’ve probably done the same thing: if you feed your pet in a certain spot in the kitchen, it will probably start to hang out in that spot."

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