Ketamine Causes Long-Lasting Changes in Brain Function in Young Mice

Ketamine Causes Long-Lasting Changes in Brain Function in Young Mice

Posted: October 13, 2015

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Ketamine, an anesthetic that is being tested as a fast-acting antidepressant, causes delayed social development and changes in brain function that last into adulthood, say researchers who administered the drug to young mice.

In a study published online September 15 in Translational Psychiatry, the researchers observed how ketamine affected social behavior and cognitive functions such as attention and memory. The team was led by Steven J. Siegel, M.D., Ph.D., a 1999 NARSAD Young Investigator grantee, and lead author Lauren Nagy, of the University of Pennsylvania; it also included Chang-Gyu Hahn, M.D., Ph.D. a 2000 and 2002 NARSAD Young Investigator grantee and a 2010 Independent Investigator grantee.

Ketamine acts to block or inhibit nerve cell docking ports called NMDA receptors. They are targets of glutamate, an excitatory neurotransmitter.  The drug has been used as an anesthetic for decades. More recently, clinicians have explored it as a treatment for unresponsive depression, with very promising results at low dosages. Outside of the clinic, the “street” version of ketamine has been abused as a hallucinogenic drug. In adults, the risks of abusing ketamine are well known: psychosis is common and long-term cognitive deficits, in areas like memory formation and high order executive function, have also been observed. But little is known about how the drug, particularly in very low doses, affects the cognitive function of teens and young adults – the most common group of abusers.

For this reason, the team of researchers utilized mice as a model system to study how ketamine use in a juvenile affects development. The researchers routinely administered ketamine to juvenile mice to mimic chronic drug abuse.  Dr. Siegel explains that the dose given was 1/5th of an anesthetic dose, “one that does not cause sedation and therefore we think similar to those used both recreational use and in depression protocols.” The mice were then assessed as adolescents and again adults. The researchers probed social interactions, spatial memory, and brain function to determine if the drug altered development.

They found that, after juvenile ketamine use, distinct abnormalities in brain function persisted well into adulthood. For example, the team measured so-called “theta oscillations” in the brain that reflect, at least in part, how the brain reacts to an experience. After ketamine exposure, the mice had reduced theta activity, consistent with their overreaction to non-threatening events.

Similarly, the mice showed delayed social development after ketamine use. Normally, interactions between mice become shorter as they age; for ketamine-treated mice, social interactions lasted just as long for adults as for adolescents, suggesting that these mice may fail to respond to cues that terminate social contact.

Despite these differences, the researchers were surprised that they were unable to find the dramatic cognitive deficits that they had expected, based on the data for ketamine use in adult mice. For example, spatial memory was unaffected by ketamine use. The researchers suggest that this may be due to the increased plasticity of the adolescent brain. Future research is likely to explore other aspects of cognitive function and memory in an effort to comprehensively identify how ketamine use affects the juvenile brain.

Read the paper.

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