Neuropharmacology of Synthetic Cathinones

Abstract

Synthetic cathinones are derivatives of the naturally occurring compound cathinone, the main psychoactive ingredient in the khat plant Catha edulis. Cathinone is the β-keto analog of amphetamine, and all synthetic cathinones display a β-keto moiety in their structure. Several synthetic cathinones are widely prescribed medications (e.g., bupropion, Wellbutrin^®), while others are problematic drugs of abuse (e.g., 4-methylmethcathinone, mephedrone). Similar to amphetamines, synthetic cathinones are psychomotor stimulants that exert their effects by impairing the normal function of plasma membrane transporters for dopamine (DAT), norepinephrine (NET), and 5-HT (SERT). Ring-substituted cathinones like mephedrone are transporter substrates that evoke neurotransmitter release by reversing the normal direction of transporter flux (i.e., releasers), whereas pyrrolidine-containing cathinones like 3,4-methylenedioxypyrovalerone (MDPV) are potent transporter inhibitors that block neurotransmitter uptake (i.e., blockers). Regardless of molecular mechanism, all synthetic cathinones increase extracellular monoamine concentrations in the brain, thereby enhancing cell-to-cell monoamine signaling. Here, we briefly review the mechanisms of action, structure-activity relationships, and in vivo pharmacology of synthetic cathinones. Overall, the findings show that certain synthetic cathinones are powerful drugs of abuse that could pose significant risk to users.

Keywords: Cathinone; Dopamine; Monoamine; Serotonin; Stimulant; Transporter.

Fig. 1

Chemical structures of synthetic cathinones. Synthetic cathinones are β-keto amphetamines. Diethylpropion, bupropion, and pyrovalerone are FDA-approved medications in the USA, whereas mephedrone, methylone, and MDPV are abused drugs that were first encountered in so-called “bath salts” products

Fig. 2

Dose-response effects for cocaine and amphetamine in DAT uptake and release assays in rat brain synaptosomes. Data are depicted as mean ± SD for N = 3 experiments performed in triplicate. Note that cocaine and amphetamine both fully inhibit [³H]dopamine uptake (left panel), whereas only the transporter substrate amphetamine evokes fully efficacious release of [³H]MPP⁺ (right panel)

Fig. 3

Effects of monensin on [³H]MPP⁺ efflux induced by MDPV or mephedrone in HEK cells expressing human DAT. Vehicle (VEH, physiological buffer) or 10 μM monensin (MON) was added to the perfusion solution at 4 min, whereas 10 μM MDVP or 10 μM mephedrone (MEPH) was added at 12 min. Data are mean ± SD for N =3 experiments performed in triplicate. Note than MON has no effect on efflux produced by MDPV (left panel) but markedly enhances efflux produced by the substrate MEPH (right panel). * denotes significance with respect to VEH + MEPH group, P < 0.05

Fig. 4

Effects of reserpine pretreatment on extracellular dopamine responses produced by MDPV or mephedrone in rats undergoing microdialysis in nucleus accumbens. Rats received 5 mg/kg i.p. reserpine 24 h prior to microdialysis testing. Rats received i.v. injections of MDPV or mephedrone (MEPH) at time zero and 60 min later. Data are mean ± SEM for N = 6 rats/group, depicted as % basal calculated from three preinjection samples. Basal dopamine concentrations in control and reserpinized rats were 3.98 ± 0.88 and 1.44 ± 0.22 pg/μL, respectively. Note that reserpine reduces dialysate dopamine responses produced by the blocker MDPV (left panel), without altering effects of the substrate MEPH (right panel). * denotes significant difference from vehicle-treated group, P < 0.05