Ketamine, in use as an anesthetic since the 1960s, shows promise for a new indication – rapid and durable improvement in treatment-resistant depression. Its effects on depression and anxiety might be attributable to activation of a brain region known as the infralimbic prefrontal cortex, a study published online June 8 suggested.

The precise mechanism by which ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, improves treatment-resistant depression has not been identified, though the prefrontal cortex is thought to play a role in modulating depression. Reporting their findings online in the Proceedings of the National Academy of Sciences, Dr. Manabu Fuchikami and his colleagues targeted the infralimbic prefrontal cortex (IL-PFC) for selective activation by ketamine and by optogenetic stimulation.

Dr. Fuchikami of the department of psychiatry at Yale University in New Haven, Conn., and his coinvestigators placed microinfusions of ketamine into several different areas of the prefrontal cortex of rat subjects. Control rats received infusions of muscimol, a chemical that inactivates neurons in these brain regions, before receiving ketamine (Proc. Natl. Acad. Sci. U.S.A. 2015 June 8 [doi:10.1073/pnas.1414728112]).

After ketamine microinfusion with or without muscimol, the rodents underwent behavioral testing to assess the degree of depression or anxiety they displayed in situations of stress. The rats whose IL-PFC regions were activated by ketamine showed significantly less depression and anxiety (P < 0.05) as measured by the behavioral testing.

Confirmation that IL-PFC activation is responsible for ketamine’s antidepressant effects in the rat subjects was provided by optogenetic testing. In optogenetics, a molecule that causes neuronal activation in response to light of a particular wavelength is inserted into specific cells, in this case, by means of a customized virus. These neurons can then be activated selectively with pulsating light. “We also found that optogenetic stimulation of the IL-PFC produced rapid and long-lasting antidepressant and anxiolytic effects,” said Dr. Fuchikami and colleagues.

The IL-PFC optogenetic stimulation group was compared with a control group receiving light without optogenetic stimulation. A separate group of rats received optogenetic stimulation of a different brain region, the prelimbic prefrontal cortex (PrL-PFC). The IL-PFC stimulation group saw significant anxiolytic and antidepressant effects, compared with the control group (range, P = 0.037; P < 0.01 for various behavioral tests). No significant changes were seen in the PrL-PFC treatment group, compared with controls.

The synaptic responses seen with optogenetic stimulation of the IL-PFC also were similar to those seen when ketamine was systemically administered. “IL-PFC stimulation is necessary and sufficient for the antidepressant behavioral actions of ketamine,” the researchers said.

The study was supported by the National Institute of Mental Health, Yale University, and the state of Connecticut. The authors reported no conflicts of interest.

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