Researchers Identify Chemical that Eases Signs of Opiate Withdrawal

The neurotransmitter dopamine has been linked to pleasure and reward in many ways: food, sex, gambling and drugs of abuse have all been shown to rely on the actions of dopamine within certain brain circuits. Researchers are now finding that dopamine-or rather a lack of dopamine-might also be linked to depression.

A team of McLean Hospital researchers led by Elena Chartoff, PhD, and William Carlezon, PhD, report in a recent issue of The Journal of Neuroscience (abstract) that a lack of dopamine may contribute to the depression that accompanies withdrawal from the opiate morphine. Chartoff and colleagues found that a chemical that partially mimics dopamine-termed a dopamine D1 receptor agonist-greatly reduces the incidence of morphine withdrawal signs in rats. Importantly, this chemical did not alter behaviour in rats that were not dependent on morphine or experiencing morphine withdrawal. Withdrawal from opiates occurs in two stages: an immediate, intensely agonising period of physical symptoms and a prolonged period of psychological discomfort, including depression and anxiety.Carlezon, director of the Behavioural Genetics Laboratory at McLean Hospital, explains that these findings are important because the D1 agonists might provide much-needed treatment for people addicted to such drugs as morphine or heroin, who are trying to become and remain drug-free.Addiction treatment specialists agree that the findings are significant. “The depression that can develop in opiate addicts as they struggle to remain drug-free is one of the hardest hurdles to surmount and often results in relapse,” says Bruce Cohen, MD, PhD, president and psychiatrist in chief emeritus of McLean Hospital. “The identification of an effective treatment for opiate withdrawal symptoms could have a strong impact on the number of people who are able to stop their drug use successfully without relapsing multiple times.”Chartoff, an instructor in psychiatry at McLean Hospital and lead author on the paper, says she and her team were not completely surprised by the behavioural effects of the D1 receptor agonist given that a common feature of withdrawal from most drugs of abuse is a decrease in the levels of dopamine in the brain. She noted, however, that this is the first research to specifically show that a D1 receptor agonist blocks signs of morphine withdrawal. Chartoff and her team demonstrated this in two ways. First, they used a behavioural paradigm called “place conditioning” in which rats were conditioned to associate one environment with a rewarding or aversive state and a second environment with a neutral state. After learning a particular association, the rats were allowed free access to both environments. Knowing that they would spend more time in environments that they associated with reward and less time in areas that they associated with aversion, the researchers recorded how much time the rats spent in each environment. The researchers found that morphine-dependent rats who were administered naloxone, a drug that blocks the receptors on which morphine acts, caused strong place aversions and the rats avoided the environment previously paired with naloxone. However, when the D1 receptor agonist was co-administered with naloxone, place aversions were completely blocked. In fact, these rats found a higher dose of the D1 receptor agonist rewarding. Secondly, Chartoff’s team showed that the D1 receptor agonist reduced the incidence of physical withdrawal signs in morphine-dependent rats, suggesting that activation of D1 receptors can have beneficial effects on both the physical symptoms and the psychological discomfort of opiate withdrawal.What was surprising, Chartoff says, was that the D1 agonist had no effect on the rats unless they were dependent on (addicted to) morphine. “Since dopamine is considered to be an important reward molecule, we thought that the D1 receptor agonist might have rewarding effects,” says Chartoff.The reasons for the effectiveness of the D1 receptor agonist in alleviating signs of morphine withdrawal are not fully understood, although some clues emerged in this study. The McLean researchers examined how the D1 receptor agonist regulated two proteins, CREB and GluR1, in the brain. These proteins have received considerable attention in the last several years because they are thought to regulate mood and vulnerability to addiction. In this study, the researchers showed that CREB activity is increased during morphine withdrawal whereas GluR1 activity is increased after treatment with the D1 receptor agonist. GluR1 is important for excitatory neurotransmission-the primary means of nerve cell communication in the brain. Changes in the way the brain communicates can have profound implications for behavior and drug addiction. “This work opens up exciting new avenues of research for us to follow,” says Chartoff. “We plan to examine if the D1 receptor agonist has its beneficial effects by altering GluR1 and excitatory neurotransmission. We also hope to investigate whether this chemical can be tested clinically for the treatment of opiate withdrawal.”(Source: The Journal of Neuroscience: McLean Hospital/Harvard University: July 2006).