25B‐NBOMe, a novel N‐2‐methoxybenzyl‐phenethylamine (NBOMe) derivative, may induce rewarding and reinforcing effects via a dopaminergic mechanism: Evidence of abuse potential

Abstract

An increasing number of N-2-methoxybenzyl-phenethylamine (NBOMe) derivatives are being misused worldwide, including the potent hallucinogen 2-(4-bromo-2,5dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25B-NBOMe). However, the number of studies characterizing the abuse potential and psychopharmacological properties of 25B-NBOMe is limited; thus, we examined its rewarding and reinforcing effects using conditioned place preference (CPP) and self-administration (SA) tests. Pretreatment with SCH23390 (SCH), Haloperidol (HAL), and ketanserin (KS), antagonists of dopamine D1 (DRD 1), dopamine D2 (DRD 2), and serotonin 2A (5-HT 2A receptor) receptors, respectively, was utilized during a CPP test to investigate the involvement of the dopaminergic and serotonergic systems in 25B-NBOMemediated effects. We also examined the effects of 25B-NBOMe on the expression of dopamine-related proteins in the nucleus accumbens (NAcc) and ventral tegmental area (VTA). Then, we measured the dopamine level, phosphorylated CREB (p-CREB), deltaFosB (ΔFosB), and brain-derived neurotrophic factor (BDNF) in the NAcc. In addition, we explored the involvement of 5-HT 2A receptors in the 25B-NBOMeinduced head twitch response (HTR). We also examined the effects of 25B-NBOMe on brain wave activity using electroencephalography. 25B-NBOMe elicited CPP and SA. SCH and HAL blocked 25B-NBOMe-induced CPP, whereas KS did not. Moreover, 25B-NBOMe altered the DRD 1 , DRD 2 , and dopamine transporter expression and increased dopamine levels. It also induced changes in p-CREB, ΔFosB, and BDNF expression. 25B-NBOMe induced HTR and increased 5-HT 2A receptor mRNA levels, effects inhibited by KS. Furthermore, 25B-NBOMe altered delta and gamma wave activity, which was normalized by SCH and HAL. These findings show Raly James Perez Custodio and Leandro Val Sayson have contributed equally to this manuscript.

NBOMes–Highly Potent and Toxic Alternatives of LSD

“…The 25B-NBOME-elicited CPP was blocked by antagonists of D 1 -and D 2 -dopamine receptors, SCH 23390 and haloperidol, respectively, but was not affected by ketanserin, an observation indicating an important role of dopaminergic transmission in this phenomenon (Custodio et al, 2019). In the SA test performed on mice, 25B-NBOMe used at doses of 0.03, 0.1 and 0.3 mg/kg/infusion significantly increased both a number of infusions/session and an active lever pressing/session, albeit with a weaker potency than methamphetamine (Custodio et al, 2019). On the contrary, 25N-NBOMe (0.01 mg/kg/infusion) weakly increased the number of infusions/session, but not the active lever pressing/session in mice (Seo J.Y.…”

“…The HTR is widely used as a behavioral marker for hallucinogen effects in humans (Halberstadt and Geyer, 2018). 25C-NBOMe, 25I-NBOMe, and 25B-NBOMe induced an HTR response in rodents with a potency several-fold higher than their 2C counterparts, 2C-C and 2C-I (Halberstadt and Geyer, 2014;Elmore et al, 2018;Custodio et al, 2019;Herian et al, 2019). Two lines of evidence support a notion that this behavioral effect is mediated by cortical 5-HT 2A receptors.…”

“…Two behavioral tests, conditioned place preference (CPP) and self-administration (SA), are widely used in studies examining the abuse potential of drugs by analyzing their rewarding and reinforcing effects. 25I-NBOMe (0.3 mg/kg), 25B-NBOMe (1 mg/kg), and 25N-NBOMe (3 mg/kg) produced CPP in mice with a magnitude comparable to 1 mg/kg of methamphetamine (Custodio et al, 2019;Jeon et al, 2019;Seo J.Y. et al, 2019).…”

“…Two lines of evidence support a notion that this behavioral effect is mediated by cortical 5-HT 2A receptors. Thus, ketanserin, a 5-HT 2A antagonist, blocked the 25B-NBOMe-evoked HTR and normalized 5-HT 2A mRNA levels in the mouse prefrontal cortex upregulated by a prolonged administration of the drug (Custodio et al, 2019). Gatch et al (2017) tested 25B-NBOMe, 25C-NBOMe, and 25I-NBOMe for discriminative stimulus effects similar to a prototypical psychedelic/hallucinogen DOM and to an empathogen, 3,4-methylenedioxymethamphetamine (MDMA).…”

“…et al, 2019). In the second study, mice were repeatedly treated with 25B-NBOMe (1 mg/kg) for 7 days; they were sacrificed 30 min after the last injection (Custodio et al, 2019). Results of these studies are, however, not uniform.…”