Nerve-Cell Growth During Abstinence From Methamphetamine May Promote Reinstatement of Drug Use in Rats
This research found:
- The generation of new nerve cells (i.e., neurogenesis) that occurs during abstinence from methamphetamine in a brain region related to memory and learning may promote relapse-like behavior.
- In rats, inhibition of neurogenesis during abstinence prevented reinstatement of drug use.
Many people with methamphetamine and other drug use disorders relapse after a period of abstinence, especially if they return to places where they previously used the drug. This phenomenon is known as context-driven relapse. Two studies by Ms. Melissa H. Galinato and colleagues at the University of California, San Diego, and other institutions have shed light on a mechanism that may contribute to context-driven relapse to methamphetamine use.
“New findings from our lab show that neurogenesis—the generation of new neurons in the adult brain—in the hippocampus may strengthen memories tied to drug-seeking behavior in rodents with methamphetamine addiction-like behavior,” says Dr. Chitra Mandyam, senior investigator of the two studies. These findings suggest new approaches for reducing relapse risk. Says Dr. Mandyam, “We also demonstrated that inhibiting neurogenesis during abstinence with a small synthetic molecule prevented context-driven drug-seeking.”
Neurogenesis can occur even during adulthood and is an essential process for learning. For example, newly formed circuits may link rewards, such as food or a drug, to reward-associated memories, such as the location where the reward was received. Earlier studies in rodents had found that methamphetamine administration reduced neurogenesis in the hippocampus, particularly in a region called the dentate gyrus, which has been implicated in memory processing, storage, and retrieval. Abstinence after high methamphetamine self-administration, in contrast, increased neurogenesis in the animals’ hippocampus. However, the newborn cells (progenitors) showed some abnormal characteristics compared with those in animals never exposed to the drug (see Figure 1). Dr. Mandyam and colleagues previously showed that this increased neurogenesis of aberrant progenitor cells was tied to a higher risk of drug reinstatement.
In the new studies, Ms. Galinato, Dr. Mandyam, and colleagues investigated the impact of abstinence-driven neurogenesis in more detail. In the first set of experiments, the research team used genetically modified rats in which adult neurogenesis in the dentate gyrus could be specifically inhibited with the antiviral drug valganciclovir (Valcyte). The experiment included four stages: a 17-day self-administration phase, during which the rats were trained to self-administer methamphetamine or, as a control, sucrose; a 22-day forced abstinence phase; a 6-day extinction phase; and a 2-day reinstatement phase (see Figure 2). About half of the animals were treated with Valcyte from the end of the self-administration phase to inhibit neurogenesis. After the reinstatement tests, the researchers conducted various histological, biochemical, and electrophysiological analyses on the animals.
Rats with intact abstinence-driven neurogenesis exhibited greater methamphetamine seeking during extinction and reinstatement than did the Valcyte-treated animals. This suggests that the formation of new progenitor cells during abstinence assisted with the formation of context-driven memory and was necessary for drug-seeking behavior. Conversely, blocking neurogenesis erased context-driven drug memory in these rats.
The effect of neurogenesis on drug seeking seemed to be specific to drugs of abuse, because Valcyte treatment did not reduce reinstatement in animals trained for sucrose self-administration (see Figure 3). This specificity raises hopes that targeting neurogenesis may be a viable approach for reducing risk of relapse to drug use.
Additional biochemical and electrophysiological analyses identified some mechanisms through which abstinence-driven neurogenesis may aid memory formation. For example, animals with intact abstinence-induced neurogenesis showed changes in the levels of a protein called CaMKII in the dentate gyrus. CaMKII is associated with the formation of new neural connections (i.e., plasticity), which occurs with memory and learning. These changes were not seen when neurogenesis was blocked with Valcyte treatment. Also, animals capable of abstinence-induced neurogenesis showed evidence of abnormally high neuronal function in the dentate gyrus, which may be associated with memory formation that drives drug seeking. Again, Valcyte treatment prevented these changes, and the effect was specific to methamphetamine-administering animals.
To confirm that prevention of neurogenesis can protect against context-driven reinstatement, the research team repeated the experiments with rats that had not been genetically modified. They treated rats that self-administered high or low levels of methamphetamine with a synthetic small molecule called isoxazole-9 during the abstinence phase. Isoxazole-9 is known to alter neurogenesis in the brains of adult rodents. In rats that self-administered high amounts of methamphetamine—but not in those that self-administered low amounts of the drug—isoxazole-9 treatment blocked compulsive-like drug seeking during reinstatement. These behavioral effects again were accompanied by physiological changes in newborn dentate gyrus neurons, such as reduced numbers of progenitor cells, reduced activation and modified structure of newly formed cells, and changes in CaMKII levels as seen in the earlier experiments.
The studies’ results suggest that neurogenesis during abstinence strengthens drug-associated memories that promote context-driven reinstatement of drug use. Inhibition of neurogenesis during abstinence clears the drug-associated memories, thereby reducing reinstatement risk. However, numerous questions remain. For example, it is unclear whether interrupting neurogenesis could also protect against reinstatement for other drugs, and when this disruption must occur to be effective. An earlier study had found that blocking neurogenesis in the hippocampus before animals began drug use actually increased cocaine self-administration. Nevertheless, Dr. Mandyam says, “These studies open avenues for future clinical investigations of synthetic small molecules in preventing relapse in addicted individuals.”
These studies were supported by NIDA grant DA034140.
Galinato, M.H., Takashima, Y., Fannon, M.J., et al. Neurogenesis during abstinence is necessary for context-driven methamphetamine-related memory. Journal of Neuroscience 38(8):2029-2042, 2018.
Galinato, M.H., Lockner, J., Fannon, M.J., et al. A synthetic small molecule isoxazole-9 protects against methamphetamine relapse. Molecular Psychiatry 23(3):629-638, 2018.
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NIDA. (2019, November 20). Nerve-Cell Growth During Abstinence From Methamphetamine May Promote Reinstatement of Drug Use in Rats. Retrieved from https://www.drugabuse.gov/news-events/nida-notes/2019/11/nerve-cell-growth-during-abstinence-methamphetamine-may-promote-reinstatement-drug-use-in-rats