Ketamine Evokes Acute Behavioral Effects Via μ Opioid Receptor-Expressing Neurons of the Central Amygdala.

Abstract

Background: Ketamine has anesthetic, analgesic, and antidepressant properties, which may involve multiple neuromodulatory systems. In humans, the opioid receptor (OR) antagonist naltrexone blocks the antidepressant effect of ketamine. This mechanism may differentiate ketamine from other NMDA receptor antagonists. Animal models that reflect OR-dependent behavioral effects of ketamine may shed light on the brain regions and circuits that contribute to ketamine's antidepressant mechanism in humans.

Methods: We screened male and female wild-type mice for a behavioral response to ketamine that could be reversed by OR antagonists in several assays, including locomotor activation, analgesia, and the forced swim test. Whole-brain imaging of cFos expression in ketamine-treated mice, pretreated with naltrexone or vehicle, was used to identify brain areas that mediated ketamine/OR interactions. Region-specific pharmacological and genetic interference with μ OR (MOR) signaling was used to test predictions of whole-brain imaging results in a subset of behavioral assays.

Results: Among a series of behavioral assays, only locomotor activation was sensitive to ketamine and blocked by an MOR-selective antagonist. Locomotor activation produced by the NMDA receptor antagonist MK-801 was not OR dependent. Whole-brain imaging revealed that cFos expression in neurons of the central amygdala (CeA) showed the greatest difference between ketamine in the presence versus absence of naltrexone. CeA neurons expressing both MOR and PKCδ were strongly activated by naltrexone, and selectively interrupting MOR function in the CeA either pharmacologically or genetically blocked the locomotor effects of ketamine.

Conclusions: These data suggest that ketamine acts at MORs expressed in CeA neurons to produce acute hyperlocomotion.