Blocking the birth of new neurons helps hook rats on cocaine
John has a few snorts of cocaine, finds he can take it or leave it, and never bothers to take another hit. Jim has a few snorts of cocaine and before he knows it, his whole life revolves around getting more of the white powder, until his job, his marriage, his health are gone. Why? The answer may lie in one of the most exciting neuroscience discoveries of the last fifty years: the finding that new neurons are born in the adult brain.
During the past decade we’ve learned a lot about the function of these newborn neurons, revealing their possible role in psychiatric and neurological diseases such as mood disorders, schizophrenia and epilepsy. The promise of this research is extraordinary. We may be on the verge of understanding, treating or even preventing life-crushing brain-based diseases — including one that affects an estimated 23 million Americans: drug and alcohol addiction.
In a recent study published in the Journal of Neuroscience, Michele Noonan, a University of Texas neuroscience graduate student in the lab of Amelia Eisch, shows that a lack of neurogenesis, or birth of new neurons, in the adult rat can actually cause drug addiction. Their team blocked neurogenesis in the hippocampus — a seat of memory — with targeted irradiation, and then tested the rats for their ability to become addicted to cocaine. They found that when fewer neurons were born in the irradiated hippocampus, rats were more vulnerable to develop cocaine addiction and were more likely to relapse. This is the strongest evidence yet that there are real biological reasons why some people might be more vulnerable to addiction than others, and gives us a better understanding of the role these little newborn neurons might play in the brain.
Neuroscience research on addiction has largely focused on the role of reward centers in the brain, and increasingly, the role of the hippocampus. In light of the discovery that new neurons are born in the hippocampus, recent studies have sought to understand how adult neurogenesis could be involved in addiction. Studies have shown many tantalizing correlations between neurogenesis in the hippocampus and addiction. Drugs of abuse such as cocaine can regulate adult neurogenesis. Enriched environments, antidepressants, and exercise -- all known to increase neurogenesis — are also associated with decreased drug taking and relapse. Stress and schizophrenia — known to decrease neurogenesis — are associated with increased drug taking and relapse. But until now, the causative link between adult neurogenesis and addiction has not been shown.
There have been clues, however. Much of the work (and debate) on neurogenesis and disease has focused on the function of newborn neurons in mood disorders such as depression. This has been a rich and controversial field, with conflicting reports and promises of imminent cures. The most convincing studies have shown a connection between stress, neurogenesis and depression: Stress can decrease neurogenesis, and antidepressants can increase neurogenesis. Such work has led to the compelling and yet still controversial “neurogenesis hypothesis for depression.” Could such a relatively tiny population of newborn neurons in the hippocampus be responsible for so much?
It has been notoriously challenging to test the function of newborn neurons because it is difficult to manipulate newborn neurons without perturbing the existing hippocampal network. Noonan et al overcame this problem by selectively irradiating the hippocampus of rats, inhibiting neurogenesis only in the hippocampus with no effect on the adult neurons or the overall network architecture and function. The rats with reduced neurogenesis in hippocampus became more addicted to cocaine than a control group: they pressed the lever for cocaine more often and more frequently, and became willing to press the lever more times for a single dose than the controls. After they became addicted, the rats went through a month of forced withdrawal, and their drug seeking behaviors were assessed. Rats with decreased neurogenesis were almost twice as likely to relapse, pointing to an interesting connection between learning and memory and addiction.
It is not surprising that addiction can be traced to an area of the brain that controls learning and memory as well as reward. This is certainly a rich and complex area of research, with emotional memory apparently centered in one particular region of the hippocampus, the ventral hippocampus. Could the newborn neurons be few in number but particularly powerful because they have a separate function from their adult counterparts? Could they shape what we remember as rewarding?
Stress has been shown to be a risk factor for addiction; perhaps the discomfort of stress motivates drug taking. But interestingly, in this study the rats did not have an increased stress response, or any evidence of other symptoms related to mood disorders, such as depression or anxiety. The authors conclude that there is a direct connection between neurogenesis and addiction, one that does not necessarily involve stress, and it could be the tipping point, increasing the vulnerability to addiction in one person rather than another.
Based on their results and evidence from other studies on addiction and the hippocampus, the authors suggest an intriguing explanation for addiction: newborn neurons in the hippocampus inhibit the release of dopamine, one of the major chemical messengers that act as a reward signal. Thus, with fewer young neurons in the irradiated rats, more dopamine is released when cocaine is administered. With more reward signal they are more likely to become addicted and have an exaggerated memory of reward associated with taking cocaine. Thus, with an overblown feeling of reward and memory of reward in the absence of the dopamine-dampening newborn neurons, there is an increased risk of relapse. Thus this study suggests a new and intriguing role for newborn neurons in the hippocampus, lighting the way for future studies on addiction.
It also raises an enticing prospect: Some day, when we can test for the birth of these new neurons, an addiction-prone person like Jim may not have to wonder anymore whether it’s safe to take that first hit of cocaine. He’ll know that his level of neurogenesis signals clearly: that way lies disaster.
By Kristina Rehm
March 30, 2010