Hormones Play Surprising Roles

by Elizabeth Norton Lasley

July, 2006

Hunger is such a fundamental urge, and food such a vitally important reward, that the brain has a complex set of chemical messengers and receptors dedicated to appetite, eating, and energy balance. New research is showing that these messengers are involved in other kinds of reward as well.

Many brain hormones act on receptors in the hypothalamus, a brain area that, like a thermostat, regulates states including hunger and fullness, sleeping and waking, and stress. A growing amount of research shows that these substances go deeper into the brain and influence pathways involved in other forms of complex behavior, says Eric Nestler of the University of Texas Southwestern Medical Center, Dallas.

From Fat to Brain: How Leptin Improves Mood

One such multitasker is leptin, which is produced by fat cells as a gauge of the body's energy stores. In response to signals from leptin, the hypothalamus adjusts food intake by triggering feelings of hunger. But leptin receptors also appear in the hippocampus, a center of emotion and memory leading some researchers to suspect that this hormone may be involved in mood as well.

Research has shown that depressed rats have low levels of leptin, leading Xin-Yun Lu of the University of Texas Health Science Center, San Antonio, who studies feeding behavior and stress neurobiology, to wonder if leptin might play a role in the effects of anxiety and depression on appetite. She teamed up with Alan Frazer, a specialist in the actions of antidepressants, to test leptins antidepressant potential in a model of depression in rats.

After rats are exposed to various mild stressors (such as a tail pinch or overcrowding for brief periods) in an unpredictable pattern for a few weeks, they show behavioral impairments that resemble depression. For example, they drink less water flavored with sugar, which rats usually relish. This indifference is thought to mirror depression in humans, which often features a loss of interest in previously enjoyable activities.

Reporting in the January 31 issue of Proceedings of the National Academy of Sciences, Lu, Frazer, and colleagues found that when depressed rats were treated with leptin, their interest in sugar water, and presumably their mood, improved.

In a separate phase of the experiment, the team surgically delivered leptin into either the hypothalamus or the hippocampus of rats that had undergone stress. Leptin acted as an antidepressant only in the hippocampus, indicating that this effect is independent of leptins better-known role in appetite regulation via the hypothalamus.

The authors are optimistic that clinical trials in humans will soon follow. Leptin has already been tested in humans to counter obesity, and though it was unsuccessful in this context, it has proved to be safe. (Frazer speculates that obese individuals, whose bodies have excess leptin, may be resistant to this hormone in the same way that type II diabetics are resistant to insulin.)

These tests also remove the potential hurdle of drug delivery to the brain. Leptin is a peptide, a group of the building blocks known as amino acids. Peptides are usually too large to cross the fence of cells and tissue called the blood-brain barrier, but leptin does get across, ferried over by a set of molecules called transporters. Thus it has a built-in advantage as a brain medication.

Though leptins usefulness as an antidepressant has not been proved, its versatility makes sense to Lu and Frazer. There's a tendency to view a particular compound within the framework of what it was originally discovered to do, Frazer says. But if receptors are found in other parts of the brain, its not surprising that a single substance will have many different effects.

Orexins and Addiction

When the brains reward circuitry goes awry, the result is addiction. Although nicotine, alcohol, and other drugs of abuse may initially seem to offer endless reward, their actions quickly become more sinister and extremely difficult to break.

Most recovering addicts find that even after a long time on the wagon, a particularly stressful period will have them reaching for the forbidden substance. Several teams of researchers have shown that peptides called orexins may provide one explanation.

The orexins, also called hypocretins, are secreted by the hypothalamus and have a role in regulating appetite, energy metabolism, and the cycle of sleeping and waking. More specifically, they act as an alert signal to the brain and body.

Studies have shown that stress hormones can stimulate the production of orexin. In the December 27, 2005, issue of Proceedings of the National Academy of Sciences, Luis de Lecea of the Scripps Research Institute and colleagues provided evidence that hypocretins (the researchers preferred term) play a role in reinstating drug cravings and are one route through which stress can reawaken an addiction.

When the researchers infused one type of hypocretin, called hypocretin A, into the brains of rats with an extinguished addiction to cocaine, the animals pressed a lever for cocaine significantly more often than they did without hypocretin treatment. Another group of previously addicted rats, when given a mild electrical shock to the foot, also increased their responses on the cocaine-delivering lever, but rats pretreated with a compound that blocks the receptor for hypocretin A did not, suggesting that the stress hormones released by the shock renewed the desire for drugs specifically through the hypocretin pathway.

In a similar study in the September 22, 2005, issue of Nature, Glenda Harris, Mathieu Wimmer, and Gary Aston-Jones of the University of Pennsylvania showed that cues associated with cocaine use in rats, such as being put in a chamber where they previously had been given the drug, reinstated drug-seeking. When given an orexin A antagonist (blocker) the rats did not renew their preference for cocaine, providing further evidence of orexins involvement.

Blocking this receptor is a promising treatment avenue for preventing relapse in recovering addicts, de Lecea says. It's a very restricted brain circuit involved in a specific aspect of addiction, and so would have few side effects, he says.

The research also explains a well-known but little-studied clinical observation. People with narcolepsy, who fall asleep uncontrollably, have been shown to be deficient in orexin. These patients are sometimes treated with methamphetamine, a powerful and highly addictive stimulant, yet they never become addicted.

These individuals do not have enough hypocretin to activate brain reward circuitry, de Lecea says.

How Orexins Work

Orexins may bring about addiction by altering the activity of neurons that produce dopamine, the central chemical messenger in the brains reward system. Orexin-producing neurons in the hypothalamus send their projections, called axons, into the ventral tegmental area, a nexus in the reward pathway that is rich in dopamine-producing neurons.

Antonello Bonci and colleagues at the University of California, San Francisco, have shown that orexin neurons form points of contact, called synapses, with the dopamine neurons and send signals by means of the neurotransmitter glutamate. Reporting in the February 16 issue of Neuron, the investigators showed that orexin A coaxes specific types of glutamate receptors, called NMDA receptors, out of the dopamine-producing cell and onto the synapse.

Working with cultures, the team treated dopamine neurons first with an NMDA receptor antagonist, then with orexin. Stimulating the dopamine cells with an electric charge significantly increased the portion of the cells firing that is known to be NMDA-controlled even in the presence of the blocker. When the NMDA blocker and orexin were applied together to the cells, the response was even greater, suggesting that orexin helped the NMDA receptors avoid their antagonist by relocating them onto the synapse.

To verify a role for orexin in drug addiction, the researchers injected rats first with an orexin antagonist, then with cocaine. Normally, cocaine dramatically increases physical activity, but in the orexin-treated animals this sensitization did not occur. The researchers believe that orexins play a critical role in the brain changes that lead to addiction, recruiting NMDA receptors into the synapses formed with dopamine neurons and thereby strengthening activity at the synapse.

It's a very elegant cellular mechanism that may explain our findings on the behavioral level, says de Lecea.

Changes in the functioning of neurons, known as plasticity, show how the brain reconfigures itself in response to stimuli from the environment, for good or ill. The involvement of orexins may be one of the components that turn a reward into an addiction.

The orexin findings help explain how drugs of abuse corrupt the reward circuitry originally meant for survival, Nestler says.

Other peptides involved in eating and appetite are proving to have farther-reaching consequences. For example, in the March issue of Nature Neuroscience, Tamas Horvath and colleagues at Yale University showed that ghrelin, a hormone released from the empty stomach, acts on receptors in the hippocampus to increase synapses and increase long-term potentiation, a cellular form of memory. The team also found that rats given ghrelin showed improvement on maze memory tests.

The desire for food and the associated rewards are central not only to survival but probably to evolution as well. Hunger is a powerful motivator, driving an animal to climb higher, dig deeper, work harder for rewards it might have ignored when feeling full, Nestler says. It is wholly believable that the signaling proteins important in feeding also influence brain circuits related to reward, motivation, well-being, and memory.