DECODE-018 Dissecting the Enduring changes in the prefrontal COrtex induced by exposure to the synthetic cannabinoid JWH-018 during aDolescencE: multidisciplinary characterization of the behavioral, neurochemical, and molecular outcomes at adulthood in rats and mutant mice

Psychiatric disorders have a complex etiology involving genetic and environmental factors. Among genetic factors, a nonsynonymous single nucleotide polymorphism (SNP) rs2275163 in the gene for kynurenine 3-monooxygenase (Kmo) or a functional Val66Met SNP in the gene for brain-derived neurotrophic factor (BDNF) have been linked to higher risk of psychiatric disorders. Among environmental factors, the rising use of synthetic cannabinoids (SC) poses a major psychiatric risk by impacting the development of cortical trajectories and functions. So, SC alter aminoacidergic and dopamine (DA) neurotransmission in the prefrontal cortex (PFC), a region whose dysfunction is a hallmark of psychiatric disorders. JWH-018 is the reference SC compound and studies in adult rodents showed its reinforcing and rewarding effects. Also, the repeated exposure of adult rats to JWH-018 causes major neurochemical changes in the medial PFC (mPFC) along with aversive behaviors, transient attentional deficits, and withdrawal signs after cessation. New alarming trends show that inhalation of SC vapors by e-cigarettes is becoming popular among adolescents. However, the neurobehavioral sequelae of SC exposure during adolescence are ill defined, and innovative strategies are needed to address this issue. Preliminary data show that adult rats exposed to JWH-018 vapors during adolescence display aberrant changes in the mesocorticolimbic DA system and a loss of responsiveness of DA transmission in the mPFC to salient stimuli presented at adulthood, indicating that JWH-018 likely caused a derangement of mPFC function from proper neurodevelopment. This effect could be elicited also by SC other than JWH-018 and cause the loss of control over the salience of stimuli and the psychotic symptoms featuring the abnormal neurobehavioral repertoire of SC users.

DECODE-018 multidisciplinary project will dissect the interplay between altered mPFC function and emergence of enduring molecular, neurochemical, and behavioral changes caused by the exposure to JWH-018 during adolescence, per se or combined with genetic factors. Targets will be:

1. evaluate how adolescent exposure to JWH-018 persistently alters specific pathways (DA, BDNF, cannabinoids, kynurenic acid, glutamate) in the mPFC. To this end, rats will receive JWH-018 by inhalation to mimic smoking, the most common way of drug intake in SC users, providing a method for obtaining preclinical data with high translational value;
2. clarify how the above alterations relate to defects in cognitive/emotional/social domains;
3. use mutant Kmo(+/-) and BDNF(M/M) mice to clarify how anomalies in kynurenine metabolism and BDNF pathways underlie the enduring dysregulation of mPFC after adolescent exposure to JWH-018. By exposing the psychiatric risk deriving from the use of SC, the present project may increase life quality and expectancy of next generations, being highly relevant to the human wellbeing strategic plans.