Ketamine Responsiveness of Mice Exhibiting Anorexia‐Like Behavior Correlates With Synaptic AMPA Receptor Distribution

Anorexia nervosa is a deadly eating disorder marked by extreme food restriction, compulsive exercise, and severe weight loss. In a prior study using the activity-based anorexia (ABA) animal model of anorexia nervosa, 30 mg/kg, but not 3 mg/kg, of ketamine reduced relapse vulnerability, measured as increased food intake, increased body weight (BW), and reduced excessive wheel running, though there were individual differences in responsiveness to treatment. This study investigated whether ketamine evoked sustained changes to AMPA receptors (AMPARs) at excitatory synapses of the prefrontal cortex (PFC), and whether they might correlate with individual differences in sustained behavioral improvements. Adolescent female mice that received 30 mg/kg (N = 8) or 3 mg/kg (N = 8) of ketamine underwent two cycles of ABA induction (ABA1 and ABA2), which included acclimation to a wheel preceding food restriction, with ABA2 modeling relapse. We analyzed the distributions of PFC AMPARs at synapses of pyramidal neurons (PNs) and of GABA interneurons (GABA-INs) using electron microscopy, with 10-nm immunogold to localize AMPARs. Increased AMPARs in the cytoplasm of PN synapses correlated with better BW retention during ABA2, as well as a reduction in excessive wheel running. Increased AMPARs in PN synapses' cytoplasm and GABA-INs synapses' postsynaptic density were associated with higher food intake during recovery. These correlations fit with a previous proposal that excitatory outflow from PFC to the GABA-INs in the dorsal raphe promotes feeding, while decreased excitatory outflow from PFC to dorsal medial striatum decreases hyperactivity during ABA, both of which contribute positively toward gain of resilience against ABA.