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Séminaire - Tiziana Rubino“Adolescent cannabinoid exposure and psychosis: further insight into the molecular underpinnings”

Abstract :

 We recently demonstrated that adolescent female rats treated with delta-9-tetrahydrocannabinol (THC) show a specific vulnerability for the development
of a schizoaffective-like phenotype in adulthood. However the neurobiology of this vulnerability is still to be understood. Epigenetic processes have been widely heralded as the “missing piece” of the aetiological puzzle for psychiatric disorders. Thus we checked for the presence of various histone modifications such as histone H3 acetylation and histone H3 tri- and di- methylation at specific lysine residue in the prefrontal cortex of adolescent THC-treated animals. Among the different modifications, increased trimethylation of Lysin 9 on histone H3 (H3K9Me3, associated with transcriptional repression) was observed 2 and 24 h after the end of THC treatment.

Since histone modifications impact transcriptional activity, we then investigated the effect of adolescent THC exposure on gene expression in the prefrontal cortex. Adolescence is characterized by intense processes of neuronal refinement in which the endocannabinoid system (ECS) seems to play a crucial role, thus we focused our attention on genes closely related to the ECS or involved in synaptic plasticity.

THC exposure induced an intense and wide spread decrease in mRNA levels of the considered genes that fits well with the observed histone modifications.

These alterations might play a role in the development of the schizoaffective-like disorder induced by adolescent THC exposure.

Selected publications

1: Rubino T, Prini P, Piscitelli F, Zamberletti E, Trusel M, Melis M, Sagheddu C,Ligresti A, Tonini R, Di Marzo V, Parolaro D. Adolescent exposure to THC in female rats disrupts developmental changes in the prefrontal cortex. Neurobiol Dis. 2015 Jan;73:60-9. doi: 10.1016/j.nbd.2014.09.015. Epub 2014 Oct 2. PubMed PMID: 25281318.

2: Rainer Q, Speziali S, Rubino T, Dominguez-Lopez S, Bambico FR, Gobbi G, Parolaro D. Chronic nandrolone decanoate exposure during adolescence affects emotional behavior and monoaminergic neurotransmission in adulthood. Neuropharmacology. 2014 Aug;83:79-88. 

3: Zamberletti E, Beggiato S, Steardo L Jr, Prini P, Antonelli T, Ferraro L, Rubino T, Parolaro D. Alterations of prefrontal cortex GABAergic transmission in  the complex psychotic-like phenotype induced by adolescent delta-9-tetrahydrocannabinol exposure in rats. Neurobiol Dis. 2014 Mar;63:35-47. 

4: Rubino T, Parolaro D. Cannabis abuse in adolescence and the risk of psychosis: a brief review of the preclinical evidence. Prog Neuropsychopharmacol Biol Psychiatry. 2014 Jul 3;52:41-4. 

5: Realini N, Vigano' D, Guidali C, Zamberletti E, Rubino T, Parolaro D. Chronic  URB597 treatment at adulthood reverted most depressive-like symptoms induced by adolescent exposure to THC in female rats. Neuropharmacology. 2011 Feb-Mar;60(2-3):235-43. 

Scientific focus :

Dr. Rubino’s career-long interest is represented by drugs of abuse. Her degree dissertation was about opioid receptor alterations in morphine tolerance. Since then her attention is focused on the molecular mechanisms underlying tolerance and dependence to different drugs of abuse. At the beginning she studied opioid tolerance and showed that modifications in the amount of G proteins after chronic morphine treatment or the continuous infusion of selective opioid peptides represents part of the molecular underpinnings of opioid tolerance.

A further change in G protein amounts that paralleled the behavioral manifestations of the abstinence syndrome was observed during opioid withdrawal strengthening the key role of G proteins in adaptation events following chronic treatment.

She began working in the cannabinoid field in 1994 publishing on cannabinoid/opioid interaction at the CNS level. Then she focused her attention on the cellular effects in the CNS of in vivo chronic administration of natural and synthetic cannabinoids. Besides the demonstration of the occurrence of behavioral tolerance and physical dependence to natural, synthetic and endogenous cannabinoids, she focused her attention on the cellular mechanisms underlying these phenomena, showing the relevance in specific brain areas of the alterations in receptor number and efficiency, and in cyclic AMP cascade.

Recently, with a double approach (genetic and pharmacological) she demonstrated the relevance of the Ras/ERK cascade in the molecular events occurring after chronic THC treatment. Finally, she focused her attention on a more clinically relevant topic, that is to clarify the possible role that the cannabinoid system plays in the neurobiology of anxiety, in order to have new insights for the potential therapeutic use of cannabinoid compounds in anxiety treatment.