Characterization Of The Neurochemical And Behavioral Effects Of The Phenethylamine 2-Cl-4,5-Mdma In Adolescent And Adult Male Rats

Gessica Piras; Cristina Cadoni; Francesca Caria; Nicholas Pintori; Enrica Spano; Maksims Vanejevs; Anastasija Ture; Graziella Tocco; Nicola Simola; Maria Antonietta De Luca

doi:10.1093/ijnp/pyae016

Characterization Of The Neurochemical And Behavioral Effects Of The Phenethylamine 2-Cl-4,5-Mdma In Adolescent And Adult Male Rats

Int J Neuropsychopharmacol. 2024 Mar 28:pyae016. doi: 10.1093/ijnp/pyae016. Online ahead of print.

Affiliations

¹ Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
² Institute of Neuroscience, National Research Council of Italy, Cagliari, Italy.
³ Latvian Institute of Organic Synthesis, Riga, Latvia.
⁴ Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy.

PMID: 38546531
DOI: 10.1093/ijnp/pyae016

Abstract

Background: The proliferation of Novel Psychoactive Substances (NPS) in the drug market raises concerns about uncertainty on their pharmacological profile and the health hazard linked to their use. Within the category of synthetic stimulant NPS, the phenethylamine 2-Cl-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA) has been linked to severe intoxication requiring hospitalization. Thereby, the characterization of its pharmacological profile is urgently warranted.

Methods: By in vivo brain microdialysis in adolescent and adult male rats we investigated the effects of 2-Cl-4,5-MDMA on dopamine (DA) and serotonin (5-HT) neurotransmission in two brain areas critical for the motivational and reinforcing properties of drugs, the nucleus accumbens (NAc) shell and the medial prefrontal cortex (mPFC). Moreover, we evaluated the locomotor and stereotyped activity induced by 2-Cl-4,5-MDMA, and the emission of 50-kHz ultrasonic vocalizations (USVs) to characterize its affective properties.

Results: 2-Cl-4,5-MDMA increased dialysate DA and 5-HT in a dose-, brain area-, and age-dependent manner. Notably, 2-Cl-4,5-MDMA more markedly increased dialysate DA in the NAc shell and mPFC of adult than adolescent rats, while the opposite was observed on dialysate 5-HT in the NAc shell, with adolescent rats being more responsive. Furthermore, 2-Cl-4,5-MDMA stimulated locomotion and stereotyped activity in both adolescent and adult rats, although to a greater extent in adolescents. Finally, 2-Cl-4,5-MDMA did not stimulate 50-kHz USV emissions.

Conclusions: This is the first pharmacological characterization of 2-Cl-4,5-MDMA demonstrating that its neurochemical and behavioral effects may differ between adolescence and adulthood. These preclinical data could help understanding the central effects of 2-Cl-4,5-MDMA, by increasing awareness on possible health damage in users.

Keywords: Novel Psychoactive Substances; addiction; dopamine; serotonin; ultrasonic vocalizations.