Neurochemical and Behavioral Characterization after Acute and Repeated Exposure to Novel Synthetic Cannabinoid Agonist 5-MDMB-PICA

Abstract

Since the early 2000s, herbal mixtures containing synthetic cannabinoids (SCs), broadly known as Spice/K2, have been marketed as a legal marijuana surrogate and have become very popular among adolescents. Adolescence is a critical period of development, which is associated with an increased vulnerability to the central effects of drugs. Despite growing concerns about the negative effects of the use of SCs, newly synthetized compounds are increasingly detected in drugs seized by the authorities, posing a serious threat to public health. 5F-MDMB-PICA has been recently detected and classified as a highly potent agonist of CB1 and CB2 cannabinoid receptors. Here, we first investigated the rewarding properties of 5F-MDMB-PICA in C57BL/6 adolescent and adult mice by in vivo brain microdialysis. Data showed that acute administration of a selected dose of 5F-MDMB-PICA (0.01 mg/kg i.p.) stimulates the release of dopamine in the nucleus accumbens shell of adolescent, but not of adult, mice. To further investigate the consequences of repeated exposure to this dose of 5F-MDMB-PICA, a separate group of adolescent mice was treated for 14 consecutive days and evaluated for behavioral abnormalities at adulthood, starting from 7 days after drug discontinuation. Data showed that this group of adult mice displayed an anxiety-like and compulsive-like state as revealed by an altered performance in the marble burying test. Our study suggests an alarming vulnerability of adolescent mice to the effects of 5F-MDMB-PICA. These findings provide a useful basis for understanding and evaluating both early and late detrimental effects that may derive from the use of SCs during adolescence.

Adolescent self-administration of the synthetic cannabinoid receptor agonist JWH-018 induces neurobiological and behavioral alterations in adult male mice

“…Moreover, in the present study, we reported that adolescent exposure to JWH-018 by IVSA induces repetitive/compulsive-like behaviors at adulthood, as revealed by the increase of repetitive/compulsive-like phenotypes both in the nestlet shredding and marble burying tests. Consistent with the present observations, adolescent mice treated with the SCRA 5F-MDMB-PICA for 14 consecutive days displayed repetitive/compulsive-like states at adulthood, as indexed by heightened perseverative responses in the marble burying test (Musa et al 2020 ). Accordingly, Murphy et al ( 2017 ) demonstrated that chronic administration of THC during adolescence increased nestlet shredding during adulthood; however, adolescence animals showed a trend to statistical significance in burying marbles only immediately after THC treatment.…”

“…The first key finding revealed by our investigation is that adolescent male mice (i) acquired operant behavior (lever pressing) for JWH-018 with an inverted U-shaped dose–response curve; (ii) that this behavior was specifically directed at obtaining JWH-018 since it increased under a Progressive Ratio schedule of reinforcement, and was absent in vehicle mice; (iii) that JWH-018 IVSA was reduced by pretreatment of the CB1-antagonist/inverse agonist AM251. Specifically, results showed that CD1 adolescent mice acquired JWH-018 IVSA at the dose of 7.5 µg/kg/inf (Fixed Ratio 1–3), displaying higher sensitivity to this agent compared to that shown by C57BL/6 (C57) adult mice (De Luca et al 2015 ), thereby confirming the reinforcing effects of SCRAs identified in Spice/K2 products (De Luca et al 2016 ; Musa et al 2020 ). Of note is that we established a self-administration protocol for JWH-018 using a less sensitive strain of mice, which implies greater reinforcing properties of this particular SCRA with respect to those of previous generations (Martellotta et al 1998 ; Navarro et al 2001 ), and with respect to THC (Tanda and Goldberg 2003 ; Justinova et al 2005 ).…”

“…Synthetic cannabinoid receptor agonists (SCRAs) are the most used novel psychoactive substances (NPS) (Pintori et al 2017 ; Miliano et al 2018 ; EMCDDA 2019 ; Musa et al 2020 ), particularly among adolescents (Ninnemann et al 2017 ), and are posing significant medical and psychiatric risks worldwide (Palamar et al 2017 ). Compared to Δ9-tetrahydrocannabinol (THC), the principal psychoactive constituent of Cannabis, SCRAs are extremely potent full agonists of brain CBRs (De Luca et al 2016 ), inducing longer-lasting and more adverse effects than Cannabis (Atwood et al 2010 ; Cohen and Weinstein 2018 ).…”

Molecular Mechanisms of Action of Novel Psychoactive Substances (NPS). A New Threat for Young Drug Users with Forensic-Toxicological Implications

“…The effects on neuronal development have been also studied. Brain malformations have also been shown due to inhibition of Pax-6, which is necessary for the closure of the nascent neural tube, as well as CB 1 -mediated ocular malformation, lack of memory retention and hyperactivity, and inhibition of new synapses formation in hippocampal neurons [ 68 ]. Moreover, SCRAs induced hyperreflexia and myoclonias, not induced by THC, with effects prevented by the administration of CB 1 receptor antagonist/reverse agonist AM 251, while this is not the case for sensory-motor impairments [ 69 , 70 ].…”

Effects of synthetic cannabinoids on psychomotor, sensory and cognitive functions relevant for safe driving

“…Memory impairment at the Morris water maze was also described in adult mice treated with WIN55212.2 during adolescence ( 37 ). Musa et al reported a higher anxiety-like and compulsive-like state in adulthood after a 5F-MDMB-PICA exposure during adolescence ( 39 ).…”