A great deal of research has
A great deal of research has focused on candidate medications to modulate dopaminergic mechanisms through which psychomotor stimulants produce addictive effects, i.e., drugs that expressly target the DA transporter, D1-like receptor, or D2-like receptors., , However, effective dopaminergic-based pharmacotherapies to manage the widespread use of psychomotor stimulant addiction have not yet been successful, suggesting that explicitly targeting the DA transporter or individual DA receptor subtypes may be insufficient to fully blunt the addiction-related effects of cocaine., , , , , In this study, a series of metabolites of -tetrahydroprotoberberine were sterospecifically synthesized following the procedure reported in the literature with minor modifications. The results of dopamine receptor binding revealed that all have stronger affinity than the parent -THP. Further functional assay indicated that -ICP, -THB, and -DTHB are partial antagonists at D1, antagonists at D2, and agonists at D5. In view of the prominent role of dopaminergic mechanisms in cocaine’s abuse-related effects, an alternative, and perhaps more attractive approach for treating cocaine addiction may lie in the use of pharmacological agents that concurrently target both DA D1- and D2-like receptor subtypes. Their effects on cocaine self-administration and reinstatement of cocaine seeking following Polydatin are being investigated.
We thank the National Institutes of Health for financial support under grant R01-AT-006899-4.
Introduction Amphetamines are psychoactive substances and members of the phenylethylamine family, which include a broad range of substances that may be stimulant, euphoric, anorectic, or hallucinogenic agents (Carvalho et al., 2012). Amphetamine (AMPH), methamphetamine (MA), and 3,4-methylenedioxymethamphetamine (MDMA) are widely abused amphetamine-like synthetic drugs, with the basic chemical structure of phenylethylamine (Teixeira-Gomes et al., 2015). It is well-known that MA-induced neurotoxicity associated with oxidative stress, apoptosis, and microglial activation might be, at least in part, due primarily to the excessive release of dopamine neurotransmitter, accompanied by stimulation of dopamine receptors. The stimulation of dopamine receptors potentially leads to the activation of downstream pathways and ultimately results in damage of postsynaptic to the DA-terminal neurons (Xu et al., 2005). Therefore, investigators have demonstrated that blockade of dopamine receptors contributed to the protection of dopaminergic neurons against MA toxicity. Previous reports showed that not only pharmacological blockade (O\'Dell et al., 1993, Metzger et al., 2000, Angulo et al., 2004, Ares-Santos et al., 2012, Ares-Santos et al., 2013, Dang et al., 2017a), but also genetic inactivation of dopamine D1 or D2 receptor (Granado et al., 2011a, Ares-Santos et al., 2012) prevented toxic effects on DA systems induced by MA, indicating that dopamine receptors are critical mediators to MA-induced neurotoxicity. Another amphetamine-type psychostimulant, 3-fluoromethamphetamine (3-FMA) is structurally categorized as a synthetic drug of substituted AMPH and characterized by fluorine at the 3 position of the phenyl group of MA. 3-FMA has been officially notified as a newly emerging designer drug in Finland, U.S.A, China, and New Zealand (EMCDDA, 2009, Kelleher et al., 2011, C.F.a.D.A, 2015, Samantha and Coward, 2016, Legislature, 2017). However, there has been no scientific information on the prevalence of 3-FMA in these countries. 3-FMA has been associated with increased risk of death in Finland, England and Wales (Vili et al., 2012, Statistics, 2015, Shapiro, 2016) and listed as a restricted drug in West Virginia, U.S.A (Laws, 2015). An earlier study has shown that fluorinated derivatives of AMPH exhibited psychostimulant-like properties (Marona-Lewicka et al., 1995). In addition, the behavioral and neurotoxic effects induced by 3-FMA currently remain unknown.