Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning

Abstract

Drugs that modulate serotonin (5-HT) synaptic concentrations impact neurogenesis and hippocampal (HPC)-dependent learning. The primary objective is to determine the extent to which psilocybin (PSOP) modulates neurogenesis and thereby affects acquisition and extinction of HPC-dependent trace fear conditioning. PSOP, the 5-HT2A agonist 25I-NBMeO and the 5-HT2A/C antagonist ketanserin were administered via an acute intraperitoneal injection to mice. Trace fear conditioning was measured as the amount of time spent immobile in the presence of the conditioned stimulus (CS, auditory tone), trace (silent interval) and post-trace interval over 10 trials. Extinction was determined by the number of trials required to resume mobility during CS, trace and post-trace when the shock was not delivered. Neurogenesis was determined by unbiased counts of cells in the dentate gyrus of the HPC birth-dated with BrdU co-expressing a neuronal marker. Mice treated with a range of doses of PSOP acquired a robust conditioned fear response. Mice injected with low doses of PSOP extinguished cued fear conditioning significantly more rapidly than high-dose PSOP or saline-treated mice. Injection of PSOP, 25I-NBMeO or ketanserin resulted in significant dose-dependent decreases in number of newborn neurons in hippocampus. At the low doses of PSOP that enhanced extinction, neurogenesis was not decreased, but rather tended toward an increase. Extinction of "fear conditioning" may be mediated by actions of the drugs at sites other than hippocampus such as the amygdala, which is known to mediate the perception of fear. Another caveat is that PSOP is not purely selective for 5-HT2A receptors. PSOP facilitates extinction of the classically conditioned fear response, and this, and similar agents, should be explored as potential treatments for post-traumatic stress disorder and related conditions.

Psychedelics

“…Catlow et al (2013) investigated the role of psilocybin on hippocampal neurogenesis and trace fear conditioning in rats. They found that a single low dose of psilocybin (0.1 mg/kg, once per week for 1 month) led to more rapid extinction of cued fear conditioning and increased neurogenesis compared with saline control.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Therefore, it is only recently that proper guidelines for psychedelic drug research have been established and studies have begun to produce some understanding of the neurochemical events directly responsible for producing hallucinogeninduced neuroplasticity (Catlow et al, 2013;Lepack et al, 2015), although many questions still remain.…”

“…One recent study attempted to shed light on the relationship between the "therapeutic" effects of serotonergic hallucinogens and their effect of neuroplasticity by measuring the effects of varying doses of psilocybin on extinction of fear conditioning and neurogenesis in mice (Catlow et al, 2013). They demonstrated that psilocybin significantly accelerated the extinction of fear conditioning, and this was associated with a trend toward increased neurogenesis in the dentate gyrus.…”

“…They demonstrated that psilocybin significantly accelerated the extinction of fear conditioning, and this was associated with a trend toward increased neurogenesis in the dentate gyrus. Although further work is needed, one could speculate that the effects of psilocybin on neurogenesis are due to 5HT 2A receptor-mediated upregulation of BDNF (Vaidya et al, 1997), suggesting a mechanism strongly resembling that of SSRIs (Martinowich and Lu, 2008;Catlow et al, 2013;Quesseveur et al, 2013) and possibly the antidepressive mechanism of ketamine (Lepack et al, 2015).…”

The Solution to Overpopulation, The Depletion of Resources and Global Warming

“…Drugs vary by level of damage they do and the less damaging ones should be legalized in order to replace the more damaging ones. If Professor David Nutt's study on drug harms [17] is anything to go by then, according to this, currently controlled LSD and psilocybin; which actually causes neurogenesis in the hippocampus, [18] should be legalized while drugs such as alcohol and stimulants should be taxed heavier or controlled.…”