Abuse potential of methylenedioxymethamphetamine (MDMA) and its derivatives in zebrafish: role of serotonin 5HT2-type receptors

Rationale: The synthetic phenethylamines are recreational drugs known to produce psychostimulant effects. However, their abuse potential has not been widely studied. Objectives: Here, we investigated the rewarding and the hallucinatory effects of 2,5-dimetoxy-4-bromo-amphetamine hydrobromide (DOB) and para-methoxyamphetamine (PMA) in comparison with the classical 3,4-methylenedioxymethamphetamine (MDMA). In addition, the role of serotonin 5-HT2-like receptor on the abovementioned effects was evaluated. Methods: Zebrafish were intramuscularly (i.m.) treated with a wide range of doses of DOB (0.1–20 mg/kg), PMA (0.0005–2 mg/kg), or MDMA (0.5–160 mg/kg). Animals were submitted to a conditioned place preference (CPP) task, to investigation of the rewarding properties, and to the evaluation of hallucinatory behavior in terms of appearance of a trance-like behavior. The serotonin 5-HT2 subtype receptor antagonist ritanserin (0.025–2.5 mg/kg) in association with the maximal effective dose of MDMA, DOB, and PMA was given i.m., and the effect on CPP or hallucinatory behavior was evaluated. Results: MDMA and its derivatives exhibited CPP in a biphasic fashion, being PMA the most potent. This effect was accompanied, for DOB (2 mg/kg) and PMA (0.1 mg/kg), by a trance-like hallucinatory behavior. MDMA at a high dose as 160 mg/kg did not induce any hallucinatory behavior. Ritanserin significantly blocked the rewarding and hallucinatory effects suggesting the involvement of serotonin 5HT2 subtype receptor. Conclusion: Collectively, these findings demonstrate for the first time that the rewarding properties of DOB and PMA are accompanied by hallucinatory behavior through a serotonergic system and reinforce zebrafish as an emerging experimental model for screening new hallucinogens.