The neuropeptide PACAP in the hippocampal dentate gyrus (DG) mediates rapid antidepressant responses. Chronic paroxetine increased hippocampal PACAP, and blocking PACAP in the DG slowed the antidepressant effect. PACAP levels were reduced in two depression models, and knocking down PACAP in the DG caused depression-like behaviors. A single infusion of PACAP into the DG produced a rapid and sustained antidepressant effect in normal and stressed mice. Optogenetic excitation of PACAP-expressing neurons instantly elicited antidepressant responses, while inhibition induced depression-like behaviors. PACAP infusion inhibited CaMKII-eEF2 signaling and activated mTOR-BDNF signaling. Acute ketamine increased PACAP, and blocking PACAP attenuated ketamine's rapid antidepressant effect.
Fear-related disorders like phobias and PTSD involve disrupted fear extinction, leading to excessive fear. Exposure therapy, the standard treatment, fails in up to 35% of patients, and adding antidepressants offers no extra benefit. Hallucinogenic drugs, particularly MDMA and ketamine, may enhance therapy by promoting neuroplastic changes in fear circuits and reducing amygdala hyperreactivity. This review examines preclinical and clinical evidence showing these drugs can strengthen fear extinction learning and improve emotional engagement in psychotherapy, potentially outperforming current first-line treatments.
A single dose of ketamine (10 mg/kg) improved fear extinction in adolescent male mice, likely by enhancing the consolidation or recall of extinction memory. Ketamine increased activity of Akt and mTOR signaling and raised levels of GluA1 and GluN2A proteins in the hippocampus, and upregulated BDNF exon IV mRNA in both the hippocampus and prefrontal cortex. It also increased c-Fos expression in the ventral hippocampus and left infralimbic ventromedial prefrontal cortex. These findings suggest that ketamine's effects on adolescent fear extinction involve activation of hippocampal Akt-mTOR-GluA1 signaling, with the ventral hippocampus and left infralimbic prefrontal cortex as neural correlates.