Abstract
Exposure to a catastrophic event or intense stimulation can trigger fear memories, and the threatening memories persist even over a lifetime. Exposure therapy is based on extinction learning and is widely used to treat fear-related disorders, but its effect on remote fear memory is modest. Berberine, an isoquinoline alkaloid derived from Coptis chinensis or Berberis spp., has been recently reported to exert a diversity of pharmacological effects on the central nervous system, such as facilitating extinction of drug memory. Here, we explored the effect of berberine on extinction of fear memory using a classical contextual fear conditioning (CFC) paradigm, which is Pavlovian conditioning, can rapidly create fear memories related to contexts. Twenty-four hours or 30 days after CFC training, mice were subjected to context extinction (10 days) to extinguish their behaviors and treated with 12.5 or 25 mg/kg berberine intragastrically 1 or 6 h after each extinction session, followed by reinstatement and spontaneous recovery tests. The results showed that intragastric administration of 25 mg/kg berberine 1 h after extinction significantly promoted the extinction of recent and remote fear memories and prevented reinstatement and spontaneous recovery of extinguished fear in mice. These findings indicate that berberine combined with extinction training could serve as a promising novel avenue for the treatment of fear-related disorders.
Highlights
Fear response is an emotional experience necessary to adapt to the new environment
This study provides evidence for the facilitating effects of berberine on fear extinction using the classical contextual fear conditioning (CFC) paradigm
The main findings of this study are as follows: (1) oral administration of berberine 1 h after each extinction session enhanced extinction rates and reduced the reinstatement of freezing behavior in both recent and remote fear memories; (2) the positive effects of berberine enhancing the extinction memory persisted for at least 30 days; (3) delayed administration of berberine 6 h after each extinction session had no effects on extinction training, reinstatement, and spontaneous recovery of fear-associated behaviors
Summary
Fear response is an emotional experience necessary to adapt to the new environment. an exceedingly strong, persistent, and uncontrollable state of fear can lead to the development of anxiety and fear-related disorders, such as posttraumatic stress disorder (PTSD). Studies demonstrate that PTSD subjects lead to extinguished fear relapses due to impaired recall of extinction memory (Vervliet et al, 2013; Goode and Maren, 2014; Qin et al, 2021). It is easy to relapse because of the persistence of fear memories in humans and rodents, the response of previously extinguished fear will reemerge when the original US is given unexpectedly, called “reinstatement” (Haaker et al, 2014; Goode and Maren, 2019). Such responses will reoccur when a substantial amount of time has passed, called “spontaneous recovery” (Rescorla, 2004; Lacagnina et al, 2019). There is an urgent need to enhance the efficacy of exposure therapy and develop potential and effective strategies for fear-related disorders treatment
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