Posttraumatic stress disorder (PTSD) is a chronic mental disorder that occurs after experiencing a traumatic event. Patients with PTSD often have reduced hippocampal neuroplasticity and smaller hippocampal volume compared to healthy individuals. Fear extinction, the process of learning that a previously feared stimulus is no longer threatening, is impaired in PTSD. Psilocybin has been shown to promote neuroplasticity and facilitate fear extinction, suggesting its potential for PTSD treatment. A recent study used fear-conditioned mice to investigate if psilocybin could facilitate fear extinction, and whether hippocampal neuroplasticity might be involved in mediating fear extinction. The mice were divided into different groups and administered varying single doses of psilocybin (0.1 mg/kg, 0.5 mg/kg, and 2.5 mg/kg) or a vehicle control. Fear extinction training and testing were conducted in a different context from fear conditioning to assess the mice's fear response. Freezing behavior, which indicates fear, was measured as the percentage of time spent freezing during the conditioned stimulus presentation. To evaluate the effects of psilocybin on locomotor activity, an open field test (OFT) was performed to measure the total distance traveled by the mice. Golgi-Cox staining and dendrite analysis were used to examine the impact of psilocybin on dendritic structure in the hippocampus. Immunofluorescence staining was conducted to assess the number of doublecortin (DCX)-positive and bromodeoxyuridine (BrdU)-positive cells, which are markers of neurogenesis, in the hippocampal dentate gyrus. Western blotting analysis was performed to measure brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR) protein levels, which are involved in neuroplasticity. The study confirmed the hypothesis that psilocybin facilitates fear extinction in fear-conditioned mice (Figure 1). Psilocybin administration led to increased neurogenesis, dendritogenesis, and synaptogenesis in the hippocampus, as well as improved fear extinction. The therapeutic effects of psilocybin were not due to changes in locomotor activity, as assessed by the OFT. The study provides evidence for the potential therapeutic benefits of psilocybin in treating PTSD and suggests that hippocampal neuroplasticity may be involved in its mechanism of action.
Figure 1. Prior to psilocybin or vehicle treatment, mice underwent fear conditioning on Day -2, which included 5 pairings of a conditioned stimulus (CS; tone) and an unconditioned stimulus (US; foot shock). Thirty minutes before extinction training on Day 0, mice were pre-treated (i.p.) with vehicle or psilocybin (0.1 mg/kg, 0.5 mg/kg, or 2.5 mg/kg). Extinction training included 12 presentations of the CS in a new context. On Day 1, extinction testing included 12 presentations of the CS in the new context. Extinction retrieval included 4 presentations of the CS on Day 6. On Day 7, fear renewal included 4 presentations of the CS in the original context. Following this test, animals were sacrificed and their brain tissues analyzed. Among fear-conditioned mice, psilocybin 2.5 mg/kg reversed the increase in percentage of freezing time (i.e., fear), compared to vehicle-treated mice on Days 0, 1, 6, and 7.
Du Y et al. Chin Med J (Engl) 2023; Epub ahead of print. Abstract
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