Electrophysiological Actions of Synthetic Cathinones on Monoamine Transporters

Abstract

Products containing psychoactive synthetic cathinones, such as mephedrone and 3,4-methylenedioxypyrovalerone (MDPV) are prevalent in our society. Synthetic cathinones are structurally similar to methamphetamine, and numerous synthetics have biological activity at dopamine, serotonin, and norepinephrine transporters. Importantly, monoamine transporters co-transport sodium ions along with their substrate, and movement of substrates and ions through the transporter can generate measurable ionic currents. Here we review how electrophysiological information has enabled us to determine how synthetic cathinones affect transporter-mediated currents in cells that express these transporters. Specifically, drugs that act as transporter substrates induce inward depolarizing currents when cells are held near their resting membrane potential, whereas drugs that act as transporter blockers induce apparent outward currents by blocking an inherent inward leak current. We have employed the two-electrode voltage-clamp technique in Xenopus laevis oocytes overexpressing monoamine transporters to determine whether synthetic cathinones found in the so-called bath salts products behave as blockers or substrates. We also examined the structure-activity relationships for synthetic cathinone analogs related to the widely abused compound MDPV, a common constituent in “bath salts” possessing potent actions at the dopamine transporter.

N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability

“…By using the TEVC technique in X. laevis oocytes overexpressing monoamine transporters, we previously showed that transportable substrates produce large Na +dependent inward currents, whereas nontransported inhibitors do not. In fact, transporter inhibitors evoke an apparent outward current because of blockade of the endogenous transporter 'leak' current (Cameron et al, 2013;Rodriguez-Menchaca et al, 2012;Solis, 2017;Solis et al, 2012). As expected, compounds eliciting maximal release efficacy in synaptosomes (eg, N-methyl 4-MA at DAT) also produced large inward currents through hDAT.…”

“…We evaluated the electrophysiological effect of the test compounds at hDAT and hSERT in X. laevis oocytes expressing these transporters and voltage-clamped to -60 mV. As noted previously, transporter substrates induce inward depolarizing currents whereas inhibitors induce outward currents (Solis, 2017;Solis et al, 2012). Figure 2 shows the effects of 4-MA analogs on transporter-mediated currents.…”

“…Drugs targeting transporters can be divided into two types based on their mode of action: (1) 'inhibitors' bind to the orthosteric site on the transporter to block neurotransmitter uptake, whereas (2) 'substrates' bind to the orthosteric site, are subsequently transported into cells, and evoke release of neurotransmitters by reverse transport (Kahlig et al, 2005;Khoshbouei et al, 2003;Rothman and Baumann, 2006;Scholze et al, 2000). Importantly, transporter substrates and inhibitors can be discriminated based on their electrophysiological signatures, whereby substrates induce transporter-mediated inward sodium currents and inhibitors induce an apparent outward current (Cameron et al, 2013;Solis, 2017;Solis et al, 2012). Evidence shows that transporter-mediated inward currents and subsequent accumulation of substrate-type drugs in cells may be responsible for producing intracellular deficits in monoamine neurons such as inhibition of neurotransmitter synthesis and disruption of vesicular storage, leading to long-term neurotransmitter depletions (Baumann et al, 2014a;Fleckenstein et al, 2007).…”

Decoding the Structure of Abuse Potential for New Psychoactive Substances: Structure–Activity Relationships for Abuse-Related Effects of 4-Substituted Methcathinone Analogs

“…All three drugs can traverse monoamine transporters and trigger a series of intracellular events that promote monoamine neurotransmitter release [3–6]. As a group, these drugs are sometimes called “transporter substrates,” because like the endogenous neurotransmitters, they can pass from the extracellular space through the transporter channel to the intracellular space.…”

Locomotor activity and discriminative stimulus effects of five novel synthetic cathinone analogs in mice and rats

“…Limited mechanistic data for dimethylone, dibutylone, and N-ethylpentylone exist; however, data for their mono-and methyl-substituted counterparts are abundant. Dimethylone acted as an uptake inhibitor at both the dopamine transporter (DAT) and serotonin transporter (SERT) in one study (Solis, 2017), but only at DAT in another (Eshleman et al, 2018), and did not produce monoamine release (Eshleman et al, 2018). Dibutylone was 32-fold selective at the DAT over the norepinephrine transporter (NET) for blocking uptake, produced no uptake effects at the SERT, and did not produce monoamine release (Eshleman et al, 2018).…”