Ritanserin-sensitive receptors modulate the prosocial and the anxiolytic effect of MDMA derivatives, DOB and PMA, in zebrafish

• Little is known about the pharmacological effects of amphetamine derivatives.
• Zebrafish is an emerging model to study emotional behavior in an inexpensive manner.
• DOB, PMA and MDMA show prosocial and anxiolytic effect.
• 5-HT2A/C serotonin receptors block the behavioral effects.

Little is known about the pharmacological effects of amphetamine derivatives. In the present study, the effect on social preference and anxiety-like behavior of 2,5-dimetoxy-4-bromo-amphetamine hydrobromide (DOB) and para-methoxyamphetamine (PMA), in comparison with 3,4 methylenedioxymethamphetamine (MDMA) was investigated in zebrafish, an emerging model to study emotional behavior in an inexpensive and quick manner. DOB (0.05–2 mg/kg), PMA (0.0005–2 mg/kg) or MDMA (0.25–20 mg/kg), given i.m. to adult zebrafish, progressively increased the time spent in the proximity of nacre fish picture in a social preference test. However, high doses were ineffective. Similarly, in the novel tank diving and light-dark tests the compounds elicited a progressive anxiolytic effect in terms of time spent in the upper half of the tank and in the light compartment, respectively. All the above effects were interpolated by symmetrical parabolas. The 5-HT2A/C antagonist ritanserin (0.025–2.5 mg/kg) in association with the maximal effective dose of MDMA, DOB and PMA blocked both the social and anxiolytic effect. Taken together these findings demonstrate for the first time the prosocial and anxiolytic properties of DOB and PMA and focus on the mechanisms of their action through the serotonergic-like system suggesting a potential clinical application.