Rethinking chemical signals in bird brains

A group of researchers, led by Gregory Ball of the Department of Psychological and Brain Sciences, has uncovered evidence for an intriguing kind of chemical crosstalk in the brain. Their finding - that the neurotransmitter dopamine interacts with a class of receptors normally associated with a different neurotransmitter - provides an exception to a basic principle of neuroscience.

Since dopamine's discovery in 1952 by two Swedish researchers, the conventional wisdom has been that it binds uniquely to dopamine receptors. This, in turn, has been sine qua non for studying the role of dopamine in neurological disorders like Parkinson's disease as well as the neural basis of drug addiction, motivation and pleasure.

Indeed, this principle - that a neurotransmitter will only bind to its own complementary class of receptors - is a central tenet of modern neuroscience. Scientists expect that serotonin will bind to serotonin receptors, acetylcholine to acetylcholine receptors, and so on.

Nonetheless, a host of recent research has hinted that dopamine may, in fact, interact with other kinds of receptors. Until now, however, no hard evidence has yet been uncovered. Towards this goal, Ball and his colleagues chose to study one receptor, the alpha-2-adrenergic receptor, in the zebra finch brain.

The choice of a bird was not random. "Zebra finches are songbirds that possess a specialized neural circuit that controls the learning and production of song," Ball said.

The potential for dopamine to bind to other receptors seems especially likely in the brains of songbirds, including the zebra finch. The neural systems that produce the complex series of vocalizations comprising a bird's song have been mapped out in great detail.

This fact has allowed specific pathways and areas in the songbird's brain to be linked to specific aspects of a bird's song. More important to the present study, lots of dopamine and dopamine-like molecules have been shown to be highly concentrated in the bird brain's song-production areas.

One of these dopamine-like molecules is norepinephrine, which binds to alpha-2-adrenergic receptors. "There are high densities of certain noradrenergic receptor subtypes in these brain nuclei involved in song control," Ball said.

There are, however, many reasons to believe that dopamine could also bind to norepinephrine receptors. For one, dopamine and norepinephrine are chemical siblings.

Indeed, dopamine and norepinephrine are only one degree removed in the chain of neurotransmitter synthesis that takes place in neurons' cell bodies. There, enzymes turn dopamine into norepinephrine by lopping off a hydroxyl group, which consists of an oxygen and a hydrogen, and replacing it with a simple carbon group.

First, the team needed to answer a few basic questions: Does dopamine bind at all to alpha-2-adrenergic receptors? If so, how well does it bind? To figure this out, the team injected zebra finches with a radioactive alpha-2-adrenergic receptor antagonist.

In technical parlance, a receptor antagonist is a substance that binds to a particular receptor without evoking any biological response. Because it was radioactive, the injected antagonist allowed the team to pinpoint exactly where alpha-2-adrenergic receptors were located in the finch's song areas.

But it also let the researchers test their dopamine-binding hypothesis.

The key idea here is that all binding is competitive. Hundreds of molecules, each with its own affinity for a particular receptor, vie for the privilege to bind to a single receptor. Thus, if dopamine does indeed interact with alpha-2-adrenergic receptors, it should displace the radioactive antagonist.

That's exactly what the researchers observed. Dopamine, they found, has an affinity for the alpha-2-adrenergic receptor - albeit between ten and 28 times lower than norepinephrine, the receptor's "classical" binding partner.

"This means that a neurotransmitter system whose activity and release is regulated in a manner quite distinct from norepinephrine can also act upon the song system via adrenergic receptors," Ball said.

Nonetheless, the researchers cautioned that the physiological significance of dopamine's binding to this novel class of receptor is uncertain.

Interestingly, the team's results do seem to extend to non-bird brains (species-wise, that is). "We've conducted studies on this phenomenon in rats and on a cell line that expresses the human adrenergic receptor and found similar results," Ball said. "So, we do think this finding applies to mammals, including humans."