Neuropharmacology of New Psychoactive Substances (NPS): Focus on the Rewarding and Reinforcing Properties of Cannabimimetics and Amphetamine-Like Stimulants

Abstract

New psychoactive substances (NPS) are a heterogeneous and rapidly evolving class of molecules available on the global illicit drug market (e.g smart shops, internet, “dark net”) as a substitute for controlled substances. The use of NPS, mainly consumed along with other drugs of abuse and/or alcohol, has resulted in a significantly growing number of mortality and emergency admissions for overdoses, as reported by several poison centers from all over the world. The fact that the number of NPS have more than doubled over the last 10 years, is a critical challenge to governments, the scientific community, and civil society [EMCDDA (European Drug Report), 2014; UNODC, 2014b; Trends and developments]. The chemical structure (phenethylamines, piperazines, cathinones, tryptamines, synthetic cannabinoids) of NPS and their pharmacological and clinical effects (hallucinogenic, anesthetic, dissociative, depressant) help classify them into different categories. In the recent past, 50% of newly identified NPS have been classified as synthetic cannabinoids followed by new phenethylamines (17%) (UNODC, 2014b). Besides peripheral toxicological effects, many NPS seem to have addictive properties. Behavioral, neurochemical, and electrophysiological evidence can help in detecting them. This manuscript will review existing literature about the addictive and rewarding properties of the most popular NPS classes: cannabimimetics (JWH, HU, CP series) and amphetamine-like stimulants (amphetamine, methamphetamine, methcathinone, and MDMA analogs). Moreover, the review will include recent data from our lab which links JWH-018, a CB1 and CB2 agonist more potent than Δ9-THC, to other cannabinoids with known abuse potential, and to other classes of abused drugs that increase dopamine signaling in the Nucleus Accumbens (NAc) shell. Thus the neurochemical mechanisms that produce the rewarding properties of JWH-018, which most likely contributes to the greater incidence of dependence associated with “Spice” use, will be described (De Luca et al., 2015a). Considering the growing evidence of a widespread use of NPS, this review will be useful 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.

Brain Disposition of cis-para-Methyl-4-Methylaminorex (cis-4,4′-DMAR) and Its Potential Metabolites after Acute and Chronic Treatment in Rats: Correlation with Central Behavioral Effects

“…This effect resembled those previously observed with amphetamine and its analogs, such as phenethylamines/3,4-methylenedioxymethamphetamine--like drugs (Wellman et al, 2009;Pálení cek et al, 2011;López-Arnau et al, 2012;Aarde et al, 2013;Miliano et al, 2016), and is very likely attributable to the fact that cis-4,49-DMAR induces the release of biologic monoamines, particularly dopamine (Charntikov et al, 2011;Brandt et al, 2014;McLaughlin et al, 2015). The rapid appearance and rapid decline of this behavioral effect is consistent with the PK profile of the compound in the brain, although a delay of about 1 hour could be noted (Supplemental Fig.…”

“…Since no drug accumulation or increase in drug bioavailability was observed after repeated injections, pharmacodynamics adaptation mechanisms probably underlie these observations. The behavioral sensitization and hyperresponsiveness of dopaminergic neurons has already been described after repeated administration of methamphetamine, as well as with other phenethylamine derivatives (Nishikawa et al, 1983;Fukushima et al, 2007;Miliano et al, 2016).…”

4,4′‐Dimethylaminorex (“4,4′‐DMAR”; “Serotoni”) misuse: A Web‐based study

“…Both the psychoactive (including the entactogenic and nootropic properties) and the adverse effects being here described are consistent with 4,4′‐DMAR being a phenethylamine or MDMAlike compound (Bershad, Miller, Baggott, & DeWit, ; Iversen et al, ; Miliano et al, ; Schifano et al, ).…”

“…It belongs to the NPS category, which encompasses a wide number of compounds widely marketed in the “real” and “virtual” world as legal substitutes for banned drugs (Miliano et al, ) and being sometimes more harmful than their parental compounds in terms of toxicity, adverse reactions, dependence, long‐term effects (Schifano, Orsolini, Papanti, & Corkery, ), fatalities (Chiappini et al, ; Loi et al, ), and psychiatric consequences ( Martinotti et al, ).…”

1‐cyclohexyl‐x‐methoxybenzene derivatives, novel psychoactive substances seized on the internet market. Synthesis and in vivo pharmacological studies in mice

“…With increased availability, harms have increased, such as acute, sometimes fatal, poisonings (Chiappini et al, ; Loi et al, ; Dines et al, ; Zawilska & Andrzejczak, ; Bersani et al, ; Schifano et al, ), harms associated with injecting drugs (Hope et al, ), and the possibility to develop psychiatric symptoms (Martinotti et al, ; Martinotti et al, ; Bersani et al, ). Beside acute toxicological effects, many NPS seem to have addictive properties (Miliano et al, ). In addition to the “classical” NPS, which are classified into known classes of compounds (i.e., cathinones, cannabinoids, phenethylamines, opioids, tryptamines, benzodiazepines, and dissociative anesthetics), law enforcements carry out seizures of compounds that are not classified into these groups of molecules and which are labeled as “other substances” (EMCDDA, ).…”