Neuropharmacology of new psychoactive substances (NPS): focus on the rewarding properties of cannabimimetics and phenethylamines

In the last decade the trend of drug consumption has completely changed and the “classical” drugs of abuse, such as opiates, cocaine, cannabis, amphetamines, and lysergic acid diethylamide (LSD), have been replaced by several synthetic compounds. These molecules, namely New Psychoactive Substances (NPS), recently appeared in the drug market becoming very popular worldwide. NPS are designed to mimic the effects of illicit drugs, and consequently to be sold as legal alternative to them, mainly via the Internet. Scientific literature and clinical knowledge on NPS is minimal. Moreover, users are usually unaware of what they are ingesting. These factors often lead to severe cases of intoxications, difficult to understand and treat, considering that the forensic identification of these substances is complicated, also because NPS’s market adapts very quickly to changes introduced by legal controls. Besides peripheral toxicological effects, many NPS seem to have addictive properties. In order to fill the gap of scientific knowledge, the primary aim of this study was to evaluate the pharmacological effects and the abuse potential of selected NPS; in addition, this study aimed at disseminating information on the alarming consequences of using them, in order to prevent their use. Among the different classes of NPS, we chose synthetic cannabinoids (SC) and phenethylamines, that are the two most used classes, according to UNODC, Early Warning Advisory, 2014. In particular, we studied the pharmacological profile of third generation SC (AK-B48, BB-22, 5F-PB-22, 5F-AKB48, STS-135); we evaluated their in vitro affinity and agonist properties for rat and mice CB1 receptors, and their in vivo stimulant properties on dopamine transmission in the rat nucleus accumbens (NAc) shell, NAc core, and medial prefrontal cortex (mPFC). Among phenethylamines, we chose 25I-NBOMe, that is one of the most used among young people as alternative to LSD. In vivo microdialysis studies were performed to evaluate the effect of this compound on dopamine (DA) and serotonine (5-HT) transmissions, both in male and female rats, moreover, behavioral tests, such as sensorimotor studies, body temperature evaluation and nociception test, were performed. The main results of this work were that third generation cannabinoids, BB-22, 5F-PB-22, 5F-AKB-48, and STS-135 are full agonists of CB1 receptors and they are more potent compared to AKB-48, which belongs to the same generation but appeared earlier in the market, as well as compared to JWH-018, belonging to the first generation of SC. They all affect DA transmission selectively in the NAc shell, displaying a putative abuse liability; furthermore, we demonstrated that the phenethylamine 25I-NBOMe is more active in females, compared to males, in increasing DA transmission in NAc shell and in the mPFC; behavioral data showed that this compound caused visual alterations in both sexes, whereas core temperature in females is heavily affected, compared to males; indeed, the highest dose tested exerts an analgesic effect prominent in male rats, compared to female rats. Finally, we disseminated the toxicological effects related to the consumption of NPS by organizing conferences in some high schools, and sharing this information on Facebook and on the blog http://infonuovedroghe.blogspot.it/. Considering the growing evidence of the widespread use of NPS, this work helps us to understand the new trends in the field of drug reward and drug addiction by revealing the rewarding properties of NPS, and will be helpful to gather reliable data regarding the abuse potential of these compounds. Further investigations in the future might be useful to assess if these properties can explain the high acute toxicity and the addiction liability of these compounds, as well as the cases of death reported after their ingestion.