Serotonin 5-HT2A, 5-HT2c and 5-HT1A receptor involvement in the acute effects of psilocybin in mice. In vitro pharmacological profile and modulation of thermoregulation and head-twich response.

The psychedelic 5-HT2A receptor (5HT2AR) agonist psilocybin (or the active metabolite psilocin) has emerged as potential useful drug for various neuropsychiatric diseases, with a rapid onset of therapeutic activity. However, the mechanisms responsible for such effects remain incompletely characterized. We aimed to study in vitro pharmacological profile and in vivo acute mechanism of psilocin/psilocybin. Competition binding studies with psilocin were performed in brain and cell cultures. The role of 5HT2AR, 5-HT2C receptors (5HT2CR) and 5-HT1A receptors (5HT1AR) on the psychosis-like head-twitch response (HTR) and on body temperature in mice after psilocybin administration were evaluated. Psilocin showed similar affinities for 5HT2AR (Ki: 120-173 nM), 5HT2CR (Ki: 79-311 nM) and 5-HT1AR (Ki: 152-146 nM) in human and mice brain. Psilocybin induced a dose-dependent HTR (maximal effect 17.07 ± 1.31 at 1 mg/kg i.p.) that was completely suppressed by the 5HT2AR antagonist MDL11939 (1 mg/kg). Higher doses of psilocybin (3 mg/kg) induced lower HTR (9.00 ± 0.53). The 5HT2CR antagonist SB242084 (0.1 mg/kg) increased HTR exerted by psilocybin (3 mg/kg). Psilocybin significantly raised core body temperature at low dose (0.125 mg/kg) (Emax=0.67 ± 0.15 °C), whereas a significant decrease was induced by doses over 1 mg/kg (Emax = -1.31 ± 0.16 °C). Pre-treatment with the 5HT1AR antagonist WAY100635 reversed the decrease of body temperature after psilocybin (1 mg/kg), causing hyperthermia (Emax = 0.94 ± 0.26 °C). The present work provides key findings on the 5HT2AR, 5-HT2CR and 5HT1AR involvement in the acute central effects of psilocybin. The results may be relevant for understanding the mechanism of action underlying the therapeutic effects and side effects of this psychedelic drug.

Relationship between non-functional masticatory activity and central dopamine in stressed rats.

In humans, diurnal tooth-clenching and other oral stereotyped behaviour are associated with stress/anxiety. In rodents, gnawing/biting of objects is observed during exposure to stress. Both nigrostriatal and mesocortical dopaminergic systems are involved in the development of this coping behaviour. To clarify the relationship between central dopaminergic activity and stress-induced parafunctional masticatory behaviour, using microdialysis in vivo, we assessed the changes in extracellular dopamine concentrations in both prefrontal cortex and striatum of rats subjected to a mild tail pinch. The animals were divided into two groups according to the degree of non-functional masticatory activity (NFMA) displayed during exposure to tail pinch. In prefrontal cortex, rats which displayed severe NFMA showed a greater increase in extracellular dopamine concentration in relation to basal values (Emax=184±26%) than those which did not display this coping behaviour (Emax=139± 23%) (F(NFMA) [1,86]=3·97; P<0·05) (n=17). A positive association was also found between cortical dopamine maximal value from baseline and the degree of NFMA displayed (r=0·36; P<0·05) (n=17). There were no significant differences in the tail-pinch-induced striatal dopamine increase between both groups of rats (Emax=130±10%) (n=17). These results provide further evidence in support of prefrontal dopamine playing a relevant role in the expression of stress-induced masticatory coping behaviour.