LAUSR

Long-term use of potent cannabis in adolescence increases the risk of developing psychosis [1]. Literature suggests that the serotonin 2A receptor (5HT2AR) is involved in the molecular mechanisms of psychotic symptoms [2]. Moreover, epigenetic modifications in the gen codifying for this receptor have been linked to schizophrenia disease [3]. These data suggest a link between cannabis and psychosis. Up to now, studies involving cannabis exposure and 5HT2AR are scarce and the relationship between cannabis and psychosis remains unknown. Our aim was to evaluate the status and functionality of 5HT2AR in the brain cortex of young mice chronically treated with Δ9-tetrahydrocannabinol (THC), as well as to evaluate sensorimotor gating in these mice, at basal conditions and after acute exposure to the hallucinogenic 5HT2A agonist (±)DOI. Mice were treated during young period (postnatal day 21 to postnatal day 50) with THC (10 mg/kg daily, 30 days, i.p.) or vehicle. After 5 days of washout, prepulse inhibition test (PPI) was performed in both groups at basal conditions and after acute (±)DOI injection (0.5 mg/kg, i.p., 30 minutes prior to test). Two days after the behavioural test, mice were sacrificed and brain cortices were extracted. Cortical 5HT2A protein expression and density were evaluated by western blot and [3H]ketanserin binding. Displacement curves of [3H]ketanserin specific binding (2 nM) by (±)DOI (10-11 to 10-3M) were also carried out in brain cortex membranes. Finally, specific stimulation of different Gα proteins by (±)DOI (10-5M) following a [35S]GTPγS binding assay combined with immunoprecipitation was determined in cortical membranes. Statistical analyses consisted on two-way analysis of variance (ANOVA) for the study of interactions between chronic and acute treatment in PPI test; and unpaired t-test for the comparison between THC and vehicle groups in cortical 5HT2A protein expression, density, both high and low 5HT2A logKi and (±)DOI-stimulated [35S]GTPγS binding for each G-protein subtype. Two-way ANOVA revealed a THC chronic treatment x (±)DOI treatment interaction in two of the three prepulses (82 dB: F[1,54] = 9.31, p Our results show that, in mice brain cortex, THC chronic exposure during young period induces a 5HT2AR conformation that may facilitate the development of psychosis-like states and enhances the receptor’s ability to activate specific pathways of inhibitory Gα protein subtypes. Project funded by PE de I+D+i 2013-2016 and Instituto de Salud Carlos III-Subdireccion General de Evaluacion y Fomento de la Investigacion, Spanish Ministry of Economy and FEDER (Project FIS PI13/01529).