Aromatic Bromination Abolishes the Psychomotor Features and Pro-social Responses of MDMA (“Ecstasy”) in Rats and Preserves Affinity for the Serotonin Transporter (SERT)

Abstract

The entactogen MDMA (3,4-methylenedioxy-methamphetamine, “Ecstasy”) exerts its psychotropic effects acting primarily as a substrate of the serotonin transporter (SERT) to induce a non-exocytotic release of serotonin. Nevertheless, the roles of specific positions of the aromatic ring of MDMA associated with the modulation of typical entactogenic effects, using analogs derived from the MDMA template, are still not fully understood. Among many possibilities, aromatic halogenation of the phenylalkylamine moiety may favor distribution to the brain due to increased lipophilicity, and sometimes renders psychotropic substances of high affinity for their molecular targets and high potency in humans. In the present work, a new MDMA analog brominated at C(2) of the aromatic ring (2-Br-4,5-MDMA) has been synthesized and pharmacologically characterized in vitro and in vivo . First, binding competition experiments against the SERT-blocker citalopram were carried out in human platelets and compared with MDMA. Besides, its effects on platelet aggregation were performed in platelet enriched human plasma using collagen as aggregation inductor. Second, as platelets are considered an appropriate peripheral model for estimating central serotonin availability, the functional effects of 2-Br-4,5-MDMA and MDMA on ATP release during human platelet aggregation were evaluated. The results obtained showed that 2-Br-4,5-MDMA exhibits higher affinity for SERT than MDMA and fully abolishes both platelet aggregation and ATP release, resembling the pharmacological profile of citalopram. Subsequent in vivo evaluation in rats at three dose levels showed that 2-Br-4,5-MDMA lacks all key MDMA-like behavioral responses in rats, including hyperlocomotion, enhanced active avoidance conditioning responses and increased social interaction. Taken together, the results obtained are consistent with the notion that 2-Br-4,5-MDMA should not be expected to be an MDMA-like substrate of SERT, indicating that aromatic bromination at C(2) modulates the pharmacodynamic properties of the substrate MDMA, yielding a citalopram-like compound.

Aromatic Bromination Abolishes Deficits in Visuospatial Learning Induced by MDMA (“Ecstasy”) in Rats While Preserving the Ability to Increase LTP in the Prefrontal Cortex

“…The results showed that 2-Br-4,5-MDMA completely prevented the ability of MDMA to impair visuospatial learning while maintaining the capacity of the molecule to increase prefrontal cortex LTP. These results agree with our previous findings regarding the influence of aromatic bromination of the MDMA template, as 2-Br-4,5-MDMA lacks almost all MDMA effects in vivo, highlighting the relevance of this structural modification in the alteration of the pharmacological profile of MDMA [ 14 ].…”

“…As mentioned earlier, previous findings in rat behavioral models of spontaneous psychomotor activity showed that 2-Br-4,5-MDMA may disrupt the classical effects of MDMA on spontaneous locomotion, consistently restoring control values [ 14 ]. In contrast, the results of the present study indicate that both MDMA and 2-Br-4,5-MDMA equally increase LTP in the prefrontal cortex, implying that C(2) bromination does not affect their ability to induce neuroplastic effects in that cortical area.…”

“…Nevertheless, it seems plausible to speculate about the possibility that an alteration in 5-HT availability may be a key factor sustaining the occurrence of learning performance. In this regard, despite of the fact that the mechanism of action of 2-Br-4,5-MDMA remains unknown, a substantial difference regarding the mode of action compared to MDMA should be expected; whereas MDMA acts as a substrate of SERT, 2-Br-4,5-MDMA seems to be able to bind to SERT in a way similar to antidepressants, such as citalopram [ 14 ]. Consequently, their differential effects on 5-HT availability might remain differential when extrapolated to memory performance, as aromatic bromination at C(2) abolishes the detrimental effects of MDMA, after chronic administration, in the Olton maze.…”

“…Recently, we have synthesized and pharmacologically characterized, both in vitro and in vivo, a new MDMA analogue, brominated at C(2) of the aromatic ring (2-Br-4,5-MDMA), and we found that 2-Br-4,5-MDMA exhibited higher affinity for SERT than MDMA and fully abolished both platelet aggregation and ATP release, resembling the pharmacological profile of citalopram. Moreover, in vivo evaluation in rats showed that 2-Br-4,5-MDMA lacks all key MDMA-like behavioral responses in rats, including hyperlocomotion, enhanced active avoidance conditioning responses, and increased social interaction [ 14 ].…”

Cardiovascular and temperature adverse actions of stimulants

“…The tricylic antidepressant imipramine inhibits adrenaline-mediated aggregation in human platelets in vitro and decreases platelet 5-HT 2A receptor number (G omez-Gil et al, 2004). MDMA, like the SSRI citalopram, but in relatively high concentrations, inhibits collagen induced platelet aggregation (S aez-Briones et al, 2019). All of this suggests that inhibitors of monoamine transporters tend to inhibit mediator-induced platelet aggregation, and indeed the use of SSRIs is associated with a slightly decreased risk for acute MI (Schlienger et al, 2004).…”