Effect of Psilocin on Extracellular Dopamine and Serotonin Levels in the Mesoaccumbens and Mesocortical Pathway in Awake Rats

Abstract

Psilocin (3-[2-(dimethylamino)ethyl]-1H-indol-4-ol) is a hallucinogenic component of the Mexican mushroom Psilocybe mexicana and a skeletal serotonin (5-HT) analogue. Psilocin is the active metabolite of psilocybin (3-[2-(dimethylamino)ethyl]-1H-indol-4-yl dihydrogen phosphate).In the present study, we examined the effects of systemically administered psilocin on extracellular dopamine and 5-HT concentrations in the ventral tegmental area (VTA), nucleus accumbens, and medial prefrontal cortex of the dopaminergic pathway in awake rats using in vivo microdialysis. Intraperitoneal administration of psilocin (5, 10 mg/kg) significantly increased extracellular dopamine levels in the nucleus accumbens. Psilocin did not affect the extracellular 5-HT level in the nucleus accumbens. Conversely, systemic administration of psilocin (10 mg/kg) significantly increased extracellular 5-HT levels in the medial prefrontal cortex of rats, but dopamine was decreased in this region. However, neither extracellular dopamine nor 5-HT levels in the VTA were altered by administration of psilocin. Behaviorally, psilocin significantly increased the number of head twitches. Thus, psilocin affects the dopaminergic system in the nucleus accumbens. In the serotonergic system, psilocin contribute to a crucial effect in the medial prefrontal cortex. The present data suggest that psilocin increased both the extracellular dopamine and 5-HT concentrations in the mesoaccumbens and/or mesocortical pathway.Key words psilocin; dopamine; serotonin; nucleus accumbens; ventral tegmental area; medial prefrontal cortex Native peoples in Mexico have used Psilocybe mushrooms throughout history in religious ceremonies and for healing. Naturally occurring hallucinogenic substances such as psilocybin and mescaline have been recognized for their ability to alter perception, cognition, and emotion.1,2) Both psilocin and psilocybin are hallucinogenic components of the Mexican mushroom Psilocybe mexicana and are serotonin (5-HT) analogues. Psilocin is the active metabolite of psilocybin and is considered a pharmacologically active species.3,4) A number of previous studies have examined the hallucinogenic effects of psilocybin in human volunteers. [5][6][7][8] Psilocybin produces changes in mood, disturbances in thinking, illusions, and complex visual hallucinations in healthy human volunteers. 9)Moreover, preliminary clinical trials have determined that psilocybin is effective at reducing the symptoms of obsessivecompulsive disorder 10) and is an effective anxiolytic agent in terminal cancer patients with anxiety. 11)Recent pharmacological studies suggest that the hallucinogenic effects of psilocin and psilocybin are produced mainly because these compounds act as 5-HT receptor agonists that bind 5-HT 1A , 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors with moderate to high affinity.12,13) The effects of psilocybin are blocked by pretreatment with the 5-HT 2A antagonist ketanserin, indicating that the hallucinogenic effects of psilocybin are mediated primarily by 5-HT 2A...

Exploring the effect of microdosing psychedelics on creativity in an open-label natural setting

“…Kuypers et al ( 2016 ) investigated participants after the intake of large doses of Ayahuasca, which is hardly comparable to the microdoses used in the present study. Previous research has shown a relationship between 5-HT 2A receptor activity and goal-directed behavior likely due to indirect modulation of DA release (Vollenweider et al 1999 ; Sakashita et al 2015 ; Dalley et al 2002 ; Boureau and Dayan 2011 ). Dopamine-related adaptive behavior follows an inverted U shape (van Velzen et al 2014 ), suggesting that smaller doses, such as the microdoses ingested by the participants in our current study, are more likely to move participants towards the most efficient mid-zone of the performance function than higher doses do (see Akbari Chermahini and Hommel 2012 , for an application of this rationale on the impact of dopaminergic manipulations on creativity).…”

Psilocybin lacks antidepressant-like effect in the Flinders Sensitive Line rat

“…We chose to include a high (10 mg/kg) dose, which is higher than those commonly reported in the published literature [for review see (Halberstadt and Geyer, 2018)], because of the lower 5-HT 2A affinity in rats compared with humans (Gallaher et al, 1993). Furthermore, microdialysis studies showed that dopamine levels in the nucleus accumbens (NAc) are strongly altered, selectively, by 10 mg/kg psilocin and not by 1 or 5 mg/kg (Sakashita et al, 2015). This could be relevant to its antidepressant effect, as the human doses that produce a therapeutic effect (0.30-0.35 mg/kg) have also been found to increase dopamine levels in ventral striatum (NAc and olfactory tuberculum) in human PET studies (Vollenweider et al, 1999).…”

Sex differences and serotonergic mechanisms in the behavioural effects of psilocin

“…In line with this, psilocin has been shown to induce dopamine release in the striatum in humans (Vollenweider et al, 1999) and, more recently, also in the nucleus accumbens of male Wistar rats, although only with a very high dose of 10 mg/kg of psilocin (Sakashita et al, 2015). One plausible explanation is that a 5-HT1A antagonist could unmask less significant agonism on 5-HT 1B/D receptors (Tyls et al, 2014).…”