Am J Psychiatry 161:426, March 2004
© 2004 American Psychiatric Association
Drug Dependence and Addiction, II: Adult Neurogenesis and Drug Abuse
Amelia J. Eisch, Ph.D, and
Chitra D. Mandyam, Ph.D.
Dallas, Texas
The neurobiology of addiction is traditionally thought to involve the "reward pathway" of the brain: the ventral midbrain, nucleus accumbens, and frontal cortex. However, another brain region—the hippocampus—has received renewed interest for its potential role in the initiation, maintenance, and treatment of addiction. Part of this attention is due to the fact that drugs of abuse are potent negative regulators of a striking aspect of the hippocampus: adult neurogenesis.
In the middle of last century, it was discovered that the mammalian brain can give rise to new neurons throughout adulthood. Every species of mammal examined to date—including humans—has been found to have "adult neurogenesis" in just a few discrete brain regions, including the hippocampal dentate gyrus. Adult-generated cells in the dentate gyrus have been shown to mature into hippocampal granule neurons. Of interest is that new neurons in the adult hippocampus have been proposed to be a novel participant in neuroplasticity, or the ability of the adult brain to adapt to new information and new environments.
Chronic administration of drugs of abuse as diverse as opiates, THC, and ethanol decrease hippocampal function as well as decrease the number of new cells born in the dentate gyrus. The drug-induced decrease in adult hippocampal neurogenesis also appears to require chronic administration, since acute administration does not decrease the number of new cells in the dentate gyrus. Given that all drugs of abuse examined to date decrease adult neurogenesis, it has been proposed that an understanding of how these drugs decrease adult hippocampal neurogenesis may help guide the development of treatment strategies for addiction.
Every dividing cell in the body goes through the "cell cycle," which consists of four phases. Each phase of the cell cycle can be identified with biochemical markers. Traditionally, detection of adult neurogenesis relied on exogenous markers of the S phase, or DNA synthesis phase, of the cell cycle to label and track the birth of new cells. However, a new approach to adult neurogenesis is to use biochemical markers naturally expressed by cells throughout cell division. For example, chronic morphine induces abnormally early division of dividing cells in the mouse dentate gyrus (see Figure), which may block the growth of new neurons in the hippocampus.
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Figure.
Newborn cells in the adult mouse hippocampus undergoing cell division. Cell division, or mitosis, can be identified by the characteristic "lining up" of chromosomes during metaphase followed by the "pulling apart" of the chromosomes to make two new cells during anaphase. Here dividing cells in the hippocampus are labeled for naturally occurring biochemical markers during metaphase (top row) and anaphase (bottom row). In each picture the red marker (proliferating cell nuclear antigen) labels the entire nucleus, while the green marker (phosphohistone H3) labels just the chromosomes. In the top row, note the green labeling down the middle of the cell, representing the chromosomes lining up down the middle of the nucleus during metaphase. The bottom row shows two proliferating cells and one double-labeled cell in anaphase. Note the green labeling in two separate lines down the edges of the cell on the right, representing chromosome separation during anaphase. Such approaches are being used to understand how chronic drug use decreases the number of new cells in the adult hippocampus.
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Footnotes
Address reprint requests to Dr. Tamminga, UT Southwestern Medical Center, Department of Psychiatry, 5323 Harry Hines Blvd., #NC5.914, Dallas, TX 75390-9070; Carol.Tamminga{at}UTSouthwestern.edu (e-mail).
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