FIGURE 1.

The circuit disruption underlying the hypodopaminergic state is reversed by ketamine. (A) ilPFC hyperactivity increases BLA activity. BLA excitatory drive induces RE hyperexcitability which also may be a resultant of ilPFC inputs through TRN. RE projections disrupt the vHIP activity and its connectivity with NAc. Impairment of vHIP activity decreases the GABAergic tone from NAc to VP. VP excitability is resulting from a decreased NAc inhibitory drive and increased BLA excitatory drive. The increased inhibitory output of VP inhibits VTA and leads to a hypodopaminergic state. (B) Ketamine normalizes the hypodopaminergic state by downregulating the BLA activity in response to ilPFC activity restoration. The inputs coming from BLA and ilPFC are proposed to regulate the RE activity normalization. RE may represent one important neurobiological pathway underlying the reestablishment of the vHIP and NAc connectivity. Stabilization of NAc and BLA activity decreases the activity of VP inhibitory inputs to the VTA which ultimately restores dopaminergic activity. ilPFC, the infralimbic portion of the medial prefrontal cortex; BLA, basolateral amygdala; TRN, thalamic reticular nucleus; RE, reuniens thalamic nucleus; vHIP, ventral hippocampus; NAc, nucleus accumbens; VP, ventral pallidum; VTA, ventral tegmental area. Dotted lines, decreased pathway drive.