Designer Drug, 25D-NBOMe, Has Reinforcing and Rewarding Effects through Change of a Dopaminergic Neurochemical System

Abstract

2-(2,5-Dimethoxy-4-methylphenyl)-N-(2-methoxybenzyl)_ethanamine (25D-NBOMe), an analogue of the 2C family, is a newly synthesized psychoactive substance. It acts as an agonist at the 5-HT 2A receptor and has a similar mechanism to that of NBOMe compounds. However, the pharmacological mechanism for its rewarding and reinforcing effects has not been revealed. In the present study, intravenous self-administration (IVSA) test and conditioned place preference (CPP) test were performed to investigate whether 25D-NBOMe has abuse potential. We also evaluated the effects of 25D-NBOMe on neurochemical changes using western blot analysis and microdialysis. The IVSA test revealed increased self-administration in 25D-NBOMe (0.03 mg/kg)-treated rats. In addition, the CPP test revealed rewarding effects in 25D-NBOMe (1 mg/kg)-treated mice. In the neurochemical studies, 25D-NBOMe treatment affected the expression of dopamine (DA) receptor D1 (DRD1), DA receptor D2 (DRD2), tyrosine hydroxylase, DA transporter (DAT), and phospho-DAT (p-DAT) in the nucleus accumbens (NAc). In addition, microdialysis revealed that treatment with progressively increasing doses (1, 3, and 10 mg/kg) of 25D-NBOMe increased the extracellular levels of DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the rat NAc. Taken together, our results show the abuse potential and neurochemical changes related to addictive behavior after administration of 25D-NBOMe.

Molecular and Medical Aspects of Psychedelics

“…25N-NBOMe increased place preference in male C57BL/6J mice at a dose of 3 mg/kg and also produced self-administration in Sprague Dawley rats (0.1 mg/kg/infusion) [ 44 ]. 25D-NBOMe (1 mg/kg) induced CPP and was readily self-administered (0.03 mg/kg/infusion) in rats [ 45 ].…”

“…The mechanism behind those behavioral symptoms seems to originate from a dopaminergic mechanism. 25B-NBOMe [ 37 ], 25I-NBOMe [ 46 ], 25N-NBOMe [ 44 ], and 25D-NBOMe [ 45 ] increased extracellular dopamine (DA) levels in the striatum (STR) and nucleus accumbens (NAC), the structures involved in the reward system. Furthermore, the administration of NBOMe compounds affected the protein levels of DA receptors, a hallmark of abuse potential.…”

“…Furthermore, the drug significantly reduced the expression of tyrosine hydroxylase (TH) in the NAC. 25D-NBOMe increased the expression of the dopamine receptor D1 while decreasing the expression of the D2 receptor, and downregulated DAT [ 45 ]. Taken together, these changes in dopaminergic activity, while not as potent as those induced by methamphetamine, may originate from a similar mechanism.…”

“…As mentioned earlier, 25B-NBOMe elevates extracellular levels of DA in NAC and STR, which are elements of the reward system. Unlike other psychedelics, the NBOMes have been reported to exhibit rewarding properties, inducing CPP in mice and self-administration in rats [ 44 , 45 ]. Most importantly, a study by Custodio et al [ 38 ] revealed that 25B-NBOMe also exhibited these properties in CPP and self-administration, and the effects were neutralized when using the D1 or D2 receptor antagonist, clearly suggesting the involvement of the dopaminergic system.…”

“…As mentioned earlier, 25B-NBOMe elevates extracellular levels of DA in NAC and STR, which are elements of the reward system. Unlike other psychedelics, the NBOMes have been reported to exhibit rewarding properties, inducing CPP in mice and self-administration in rats [44,45]. Most importantly, a study by Custodio et al [38] revealed that Both local [61] and systemic [62] administration of 5-HT2A/2C receptor agonists were reported to induce a dose-dependent increase in extracellular levels of GABA.…”