Abstract
Stimulant drugs, including novel psychoactive substances (NPS, formerly “legal highs”) have addictive potential which their users may not realize. Stimulants increase extracellular dopamine levels in the brain, including the reward and addiction pathways, through interacting with dopamine transporter (DAT). This work aimed to assess the molecular and atomistic mechanisms of stimulant NPS actions at DAT, which translate into biological outcomes such as dopamine release in the brain’s reward pathway. We applied combined in vitro, in vivo, and in silico methods and selected 2-diphenylmethylpiperidine (2-DPMP) as an example of stimulant NPS for this study. We measured in vitro binding of 2-DPMP to rat striatum and accumbens DAT by means of quantitative autoradiography with a selective DAT-radioligand [125I]RTI-121. We evaluated the effects of intravenously administered 2-DPMP on extracellular dopamine in the accumbens-shell and striatum using in vivo microdialysis in freely moving rats. We used dynamic modeling to investigate the interactions of 2-DPMP within DAT, in comparison with cocaine and amphetamine. 2-DPMP potently displaced the radioligand in the accumbens and striatum showing dose-dependence from 0.3 to 30 μM. IC50 values were: 5.65 × 10-7M for accumbens shell and 6.21 × 10-7M for dorsal striatum. Dose-dependent responses were also observed in accumbens-shell and striatum in vivo, with significant increases in extracellular dopamine levels. Molecular dynamics simulations identified contrasting conformational changes of DAT for inhibitors (cocaine) and releasers (amphetamine). 2-DPMP led to molecular rearrangements toward an outward-facing DAT conformation that suggested a cocaine-type effect. The present combination of molecular modeling with experimental neurobiological procedures allows for extensive characterization of the mechanisms of drug actions at DAT as the main molecular target of stimulants, and provides an insight into the role of dopamine in the molecular and neurobiological mechanisms of brain responses to stimulant NPS that have addictive potential. Such knowledge reveals the risk of addiction related to NPS use. The research presented here can be adapted for other psychostimulants that act at their membrane protein targets.
Highlights
Typical drugs of addiction, stimulants such as cocaine or amphetamine, have been known to share among them the ability to activate the brain’s reward system and increase extracellular levels of dopamine (DA) in the mesolimbic pathway, and preferentially in the nucleus accumbens (NAc) (Di Chiara and Imperato, 1988; Volkow et al, 2007)
Stimulants can share similar structural moieties, such as phenylethylamine which is a common structural feature found embedded in many stimulants like amphetamine and methylamphetamine and is found in the naturally occurring neurotransmitter dopamine (Figure 1). 2-DPMP, pipradrol and methylphenidate are structurally similar with a diphenylmethane moiety (Figure 1)
By employing a novel multi-method approach, we aimed to investigate the mechanisms of the addictive potential of new psychoactive substances (NPS) that continue to be misused with no awareness of harm, including the risk of addiction
Summary
Stimulants such as cocaine or amphetamine, have been known to share among them the ability to activate the brain’s reward system and increase extracellular levels of dopamine (DA) in the mesolimbic pathway, and preferentially in the nucleus accumbens (NAc) (Di Chiara and Imperato, 1988; Volkow et al, 2007). Extracellular DA concentrations can be increased by stimulant-related inhibition or reversal of the monoamine reuptake transporters, mainly the presynaptic dopamine transporter (DAT) which is addressed below. Stimulants can share similar structural moieties, such as phenylethylamine which is a common structural feature found embedded in many stimulants like amphetamine and methylamphetamine and is found in the naturally occurring neurotransmitter dopamine (Figure 1). Extracellular DA concentrations increase, and the acute effect is thought to associate with the user’s perception of a “high” following a stimulant dose. The faster the onset, the more pronounced the perceived “high” and the greater the addictive potential of the stimulant drug (Volkow et al, 2007)
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