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PSYCHIATRY Depression Linked to Hot Spot in BrainNucleus Accumbens Could Provide Target for Future Generation of Antidepressants A trio of waterlogged rats is providing a team of McLean Hospital researchers with clues about how the brain produces the mind-numbing state of depression. By tinkering with a cluster of neurons located in the forebrain, and specifically increasing a particular protein's activity, William Carlezon and his colleagues were able to get rats to give up on a swimming task more quickly than normal animals—a sign of depression. Blocking activity of the protein caused the rodents to continue paddling around much longer than controls, which is how rats behave on antidepressants.
"Maybe the negative effects of CREB activity in the nucleus accumbens are the body's way of fighting back against drug exposure," said William Carlezon, shown with co-authors Rachael Neve (left) and Christine Konradi. "It's a signal that is telling us—this cocaine is bad, don't take it anymore." Photo by Pam Murray What is surprising is that the brain structure, the nucleus accumbens, while known to play an active role in producing addictive behavior, has not commonly been associated with depression. "This area doesn't get a lot of attention in depression research," said Carlezon, HMS assistant professor of psychiatry at McLean Hospital. The findings are reported in the Sept. 15 Journal of Neuroscience. A Quicker FixA better understanding of the nucleus accumbens, and especially of the cAMP response element binding protein (CREB), could lead to a new and possibly speedier approach to treating depression. Most antidepressants on the market take about six weeks to work in humans. Carlezon and his colleagues found in preliminary tests that drugs designed to selectively interfere with the effects of CREB in the nucleus accumbens quelled the symptoms of depression in rats almost immediately."We think this may be a better way to treat the immediate effects of depression," he said. More research needs to be done before it can be tested in humans, but the idea of selectively blocking events in the nucleus accumbens could spark interest among pharmaceutical companies. "This is an example of a new drug target that I think makes a lot of sense," said Carlezon. The first inklings that CREB, which is widely known for its role in memory formation in the amygdala and hippocampus, might be working in the nucleus accumbens to produce depression occurred several years ago. In a series of experiments reported in 1998, Carlezon, working with HMS associate professor of psychiatry Rachael Neve, also of McLean, and colleagues, created two types of rats—one with high levels of CREB activity and one with reduced CREB activity in the nucleus accumbens. Rats with high levels of activated CREB had a negative reaction to cocaine—they avoided cages where they had previously been exposed to the drug. Rats with no CREB activity reacted more positively—they sought out cocaine-associated cages. Controls neither avoided nor preferred the drug-associated environment. The researchers suspected that the first set of rats was avoiding the cage because excess CREB in the nucleus accumbens was somehow exaggerating the negative effects of cocaine withdrawal—which in humans include symptoms of depression. To test this hypothesis, the researchers embarked on a new series of experiments. The first step was to demonstrate that CREB did indeed have its greatest effect during drug withdrawal. To show this, the researchers injected all three groups of animals with cocaine and waited until the pleasurable effects had passed and withdrawal had begun. Then they placed each animal in a cage for one hour in the hope that the delay would cause them to associate the cage only with feelings experienced during the withdrawal period. After a time away from the cage, the researchers tested the animals' preference. The experimental rats showed little change in behavior: those with excess CREB still avoided the drug-associated cage while those with no CREB preferred it. But controls displayed a change. Earlier, they had neither avoided nor preferred the drug-associated cage, but now they actively shunned it—just like the excess-CREB rats. The parallel in behavior suggested that CREB had exaggerated the negative feelings of drug hangover in the experimental rats—so much so that they overrode any positive feelings associated with drug exposure. Swimming in CirclesTo get a better idea of these negative effects and specifically to see if they included symptoms of depression, the researchers subjected the rats to a standard experiment for depression, the forced swim test. In it, rats are placed in a water-filled tank for 15 minutes. Normally, rats swim vigorously around the edge of the tank for five minutes, then more passively and desultorily for another five minutes before quitting and just floating. When tested again, they give up swimming much more quickly—after two minutes instead of ten. This change is widely accepted as a sign of learned helplessness and depression. When given antidepressants, rats will continue swimming much longer.Carlezon and his colleagues found that the excess CREB rats stopped swimming much sooner than controls, suggesting that CREB was promoting depressive behavior. Rats with reduced CREB activity swam a full minute longer than normal rodents. "Our feeling is that blocking CREB has an antidepressant type effect," said Carlezon. "And increasing CREB has a pro-depressive effect." A Molecular MiddlemanCuriously, controls exhibited higher levels of activated CREB in the nucleus accumbens after their first swim. "The stress of the swim test makes activated CREB go through the roof," he said. Carlezon believes that CREB may act as a molecular go-between for stress and depression in normal animals. "Stress is the trigger for depression, but the symptoms may be mediated by CREB," he said.In fact, CREB is known to turn on the gene for dynorphin, a protein that produces feelings of dysphoria and depression. Blocking dynorphin directly could be a strategy for fighting depression, said Carlezon. He and his colleagues gave rats an experimental drug that blocks brain receptors for dynorphin. "We found the drugs had the same effect as standard antidepressants," he said. Though their studies are still at a very early stage, he believes that dynorphin blockers may someday provide a complement to existing therapies. One of the problems associated with antidepressants such as Prozac is that they take several weeks to work, presumably because it takes that long to build up levels of neurotransmitters like serotonin in the brains of patients. A new possibility raised by Carlezon's work is that standard antidepressants may also work by dampening CREB activity in the nucleus accumbens, which takes time. Carlezon and Christine Konradi, HMS assistant professor of psychiatry at McLean, are currently investigating this proposition in studies funded by the National Institute of Mental Health. "If this is true, a good strategy might be to fight off the immediate effects of CREB in the system with dynorphin blockers," Carlezon said. "The two treatments together may be a more complete therapy. "What we'd like to do in the future is see if you can give these drugs to people who come in with depression," he said. "Do they feel better right away? Or might they make other antidepressants such as Prozac work faster?" —Misia Landau |
