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

Cristina Miliano,Maria Antonietta De Luca,Maddalena Mereu,Matteo Marti,Claudia Rimondo,Giovanni Serpelloni

doi:10.3389/fnins.2016.00153

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.

Highlights

Over the last decade, New Psychoactive Substances (NPS) have become a global phenomenon
1-benzylpiperazine induced place preference in the rat, which indicates that the compound possesses rewarding properties Intravenous methamphetamine administration produces activity in reward- and affect-related areas of the human brain including the medial orbitofrontal cortex, the rostral anterior cingulate cortex and the striatum Mephedrone induced strong feelings of craving in most users METH, but not MMC, self-administration elevated TSPO receptor density in the nucleus accumbens and hippocampus, while MMC, but not METH,self-administration decreased striatal 5-hydroxyindolacetic acid (5-HIAA) concentrations Stereospecific effects of MEPH enantiomers suggest that the predominant dopaminergic actions of R-MEPH render this stereoisomer more stimulant-like when compared with S-MEPH
The potent neuroprotective effects of MDPV extend to amphetamine, 3,4-methylenedioxymethamphetamine, and MPTP-induced neurotoxicity. These results indicate that b-ketoamphetamine drugs that are non-substrate blockers of the DA transporter (i.e., MDPV) protect against methamphetamine neurotoxicity, whereas those that are substrates for uptake by the DA transporter and which cause DA release accentuate neurotoxicity This study support the hypothesis that elevations in extracellular 5-HT in the brain can dampen positive reinforcing effects of cathinone-type drugs

Summary

Introduction

New Psychoactive Substances (NPS) have become a global phenomenon. Prior studies demonstrated that MDPV and methylone, another synthetic cathinone, increase locomotor activity in rodents (López-Arnau et al, 2012; Marusich et al, 2012; Aarde et al, 2013; Gatch et al, 2013) and enhance intracranial self-stimulation (Watterson et al, 2012, 2014; Bonano et al, 2014) and engender conditioned place preference (Karlsson et al, 2014), effects that are indicators of high abuse potential (Schindler et al, 2015).

Results

Conclusion