Cannabinoids boost neurogenesis?

New study suggests the chemicals may also act as anxiolytics and antidepressants.

By | October 14, 2005

Cannabinoids promote neurogenesis in embryonic and adult rats, and produce anxiolytic- and antidepressant-like effects, according to a new report in the current issue of The Journal of Clinical Investigation. The effects appear to contradict those seen from other studied drugs of abuse, the authors note.

"Most drugs of abuse such as nicotine, heroine, and cocaine suppress neurogenesis in these cells, but the effects of cannabinoids weren't clear. We show that cannabinoids, in fact, promote neurogenesis," study author Xia Zhang of the University of Saskatchewan in Saskatoon, Canada, told The Scientist.

During the study, Zhang and his colleagues analyzed the effect of the synthetic cannabinoid HU210, an agonist of the cannabinoid receptor CB1, on neural progenitor cells in the hippocampal dentate gyrus. They found that HU210 increased cell proliferation in vitro, and did so in vivo after chronic treatment. Antidepressants produce a similar pattern of cell proliferation, inspiring the authors to examine the influence of HU210 on behavior, explained Ronald Duman of Yale University School of Medicine in an Email.

The authors measured anxiety and depression using a novelty-suppressed feeding test and a forced swimming test. They found that, indeed, HU210 produced effects similar to those of antidepressants and anxiolytics.

Furthermore, irradiating the hippocampus blocked the agonist's effects on both neurogenesis and behavior. "This provided further support for CB1 induction of neurogenesis at a functional level," explained Duman, who did not participate in the study. HU210, like antidepressants, may produce antidepressant and anxiolytic effects by promoting neurogenesis in the hippocampus, the authors note.

Although Duman found the paper "interesting and potentially promising," he advised caution in interpreting the results. "There is limited clinical evidence demonstrating that cannabinoid administration produces an antidepressant response. Thus, it's difficult to conclude that the current studies indicate and support a therapeutic action of CB1 agonists," he said.

Duman said he's also cautious about the behavioral findings, because the novelty suppressed feeding paradigm is an anxiety model, not a depression model. In addition, the forced swim test is a test for antidepressants that is responsive to acute antidepressant treatment, he noted, not chronic administration. He added that he believes the authors also did not conduct a sufficient number of controls to demonstrate that irradiation decreased neurogenesis and blocked behavioral effects, without additionally damaging hippocampal neurons and cells in other brain regions.

"This criticism is reasonable," replied Zhang. "I'm fully aware that there are no reliable clinical studies available that examine the effects of cannabinoid on mood, but the test for antidepressants mentioned in our paper has been successfully used by several groups to examine the chronic effects," he said. Zhang added that he and his colleagues followed published control methods.

Amelia Eisch of the University of Texas Southwestern Medical Center, who was not involved in the research, found the paper "intriguing." She said she was particularly interested in the correlation between the neurogenesis findings and the behavioral effects, and the promise that HU210 may serve as a novel antidepressant. "It is especially exciting to have a study challenge the hypothesis that all drugs of abuse decrease neurogenesis," said Eisch. "That being said, I think it remains to be seen how relevant these findings are for addiction. It's not at all clear whether HU210 is an addicting drug in these animals."

In a 2001 paper, Zhang and his colleagues confirmed previous findings that chronic HU210 injection produces dependence in rodents, but for Eisch, dependence is just one aspect of addiction. "This paper urges examination of the 'rewarding' or enforcing properties of HU210. Such information would provide tantalizing insight into how drugs of abuse regulate adult neurogenesis."

Eisch added that this study also raises the question of how vasculature is involved in regulating adult neurogenesis and the correlated behavioral effects. "There is some evidence that cannabinoids can cause vessel relaxation, and thus increase blood-flow. Maybe the effect they are seeing (on neurogenesis) is secondary to an effect on the vasculature," said Eisch. "The role of the vasculature is an issue for to everyone in neurogenesis research these days."

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