Psilocybin prevents symptoms of hyperarousal and enhances novel object recognition in rats exposed to the single prolonged stress paradigm

Pharmacotherapy for stress-related psychological disorders remains inadequate. Patients who are treated with conventional pharmacological agents frequently report negligeable symptom reduction, and, in most cases, less than 50% experience full remission. Clearly, there is a need for additional pharmaceutical research into both established and novel approaches to alleviate these conditions. Over the past several years, there has been a renewed interest in the use of psychedelics to aid in the treatment of psychological disorders. Several studies have reported promising results in patients with major depression, anxiety disorders, and post-traumatic stress disorder (PTSD) following treatment with psychedelic agents such as lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), ayahuasca, ketamine, and psilocybin. However, the precise behavioral and neurobiological mechanisms for these effects remain unclear. Thus, we aimed to develop an animal model of PTSD that involved prophylactic treatment with psilocybin, a 5-HT2A agonist, that could be used to further understand the mechanisms underlying the benefit of psychedelic substances in treating these disorders. Adult male and female Sprague-Dawley rats were subjected to the single prolonged stress (SPS) paradigm, including 2 hours of physical restraint, 15 minutes of forced swim, and ether vapor exposure until loss of consciousness. Five minutes following ether-induced loss of consciousness, the rats were intraperitoneally injected with vehicle (0.9% saline) or psilocybin (1 mg/kg). One week later, the rats underwent a battery of behavioral tests, including the elevated plus maze (EPM), startle response assessment, open field testing, and novel object recognition (NOR) testing. No effects of SPS or psilocybin were observed for EPM behavior. SPS led to enhanced startle responses in males, but not females, which was prevented by psilocybin. SPS also increased locomotor activity in the open field in males, but not females, and this effect was not prevented by psilocybin. SPS had no impact on NOR memory in males, but enhanced memory in females. Interestingly, psilocybin administration, alone or in combination with SPS, enhanced NOR memory in males only. These findings support a complex interaction between the administration of psilocybin and the prevention of stress-induced behavioral sequelae that depends on both sex and the type of behavioral task

Low-dose psilocybin enhances novel object recognition but not inhibitory avoidance in adult rats

Given the recently renewed interest in using psychedelics to aid in the treatment of psychological disorders, we aimed to examine the impact of psilocybin, a 5-HT2A agonist, on learning and memory in rodents. Previous work has demonstrated that psilocybin and other 5-HT2A agonists can enhance fear conditioning, fear extinction, and novel object recognition (NOR). Thus, we predicted that low doses of psilocybin would enhance inhibitory avoidance (IA) and NOR memory. In the first experiment, adult male and female Sprague-Dawley rats underwent step-through IA training (involving 0.45, 0.65, or 1 mA scrambled footshock) and were injected intraperitoneally (i.p.) with vehicle (0.9% saline) or psilocybin (1 mg/kg) immediately afterward. Rats were tested for their IA memory two days later. In the second experiment, adult male and female Sprague-Dawley rats were acclimated to an open field apparatus for 5 minutes on Day 1. The next day, the rats were given i.p. injections of vehicle or psilocybin (0.1 mg/kg) 10 minutes before undergoing NOR training, during which they were exposed to two replicas of an identical object for 3 minutes. On Day 3, one of the objects from NOR training was exchanged for a novel object; rats were exposed to this novel object and a new replica of the object from Day 2 (i.e., familiar object) for 5 minutes. The results showed that psilocybin had no significant impact on IA memory but enhanced novel object recognition memory in both males and females. The differential impact of psilocybin on IA memory and novel object recognition could be explained by the different doses of psilocybin or the different times of drug administration used for each task. Alternatively, they may suggest that psilocybin exerts distinct effects on different types of learning

Low-dose psilocybin sex-dependently enhances fear extinction in adult rats

Fear-related psychological disorders, such as specific phobias and post-traumatic stress disorder (PTSD), represent a major public health issue. It is thought that these disorders develop, at least in part, through fear conditioning processes. Thus, treatment often involves exposure therapy, a technique based on the concept of extinction. However, this type of therapy is ineffective for many individuals. To augment extinction learning, researchers have paired exposure therapy with pharmacological agents that enhance neuroplasticity (e.g., D-cycloserine), but the results of such manipulations have been inconsistent. It is possible that psychedelics, which have been largely unexplored in their ability to enhance extinction learning, could aid in exposure therapy. Indeed, preclinical research suggests that several psychedelic substances, such as MDMA and DMT, enhance synaptic plasticity. Thus, we explored the dose-dependent effects of the 5-HT2A agonist psilocybin on fear extinction in adult rats. On Day 1, adult male and female Sprague-Dawley rats were placed in a fear conditioning chamber (Context A). Following a 3-min acclimation phase, the rats were presented with 5 tones (10-sec, 2-kHz) that each co-terminated 1-sec, 1-mA footshocks; there was a 60-sec interstimulus interval (ISI) following each tone-shock pairing. On Day 2, the rats were injected intraperitoneally with psilocybin (0.3 or 1 mg/kg) or vehicle (0.9% saline) 30 min prior to undergoing fear extinction in a novel environment (Context B). During extinction, the rats were given a 3-min acclimation phase, followed by 30 tone presentations (60-sec ISIs) without any footshock. On Day 4, rats underwent extinction recall by being placed in Context B; the test began with a 3-min acclimation phase, followed by 10 tone presentations (60-sec ISIs) without any footshock. Freezing behavior was quantified by FreezeFrame software (Actimetrics, Inc.). Analyses of freezing behavior during training and early extinction demonstrated that all rats developed strong fear of the tone. Most importantly, the low dose of psilocybin enhanced extinction learning in males but slowed extinction learning in females. This differential impact of psilocybin on extinction was maintained during extinction recall the next day. Our findings suggest that a low dose of psilocybin augments extinction learning in males, but not females. The sex-dependent nature of this effect warrants additional research