The neuropharmacology of psychostimulant cathinone derivatives used as drugs of abuse.

J.M. Martinez-Clemente, R. Lopez-Arnau, D. Pubill, E. Escubedo, J. Camarasa. University of Barcelona, Pharmacology and Therapeutic Chemistry, 08028, Spain

A decrease in the availability of chemical compounds used in the synthesis of methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) lead to the appearance in the illicit market of a new generation of designer drugs, known as “cathinones” or “beta-keto (bk)”, the latter name deriving from the characteristic presence of a ketone group in the side chain.

We have studied the neuropharmacology of three new cathinones: butylone, mephedrone and methylone, as regards their abilities to inhibit plasmalemmal and vesicular monoamine transporters. Their interaction with serotonin (5-HT) and dopamine (DA) receptors and their psychostimulant effect has also been tested.

Cathinone derivatives were synthesized in our laboratory and their purity was assessed by 1H NMR and mass spectrometry. Locomotor activity was recorded in male CD-1 Swiss mice (25-30g) for 360 min after different doses of cathinones (one-way ANOVA and Tukey tests). Monoamine uptake assays were performed in striatal or cortical purified synaptosomes from male Sprague-Dawley rats (225-250g). To assess the affinity of these compounds for monoamine transporters or receptors radioligand binding assays were carried out.

Butylone, mephedrone and methylone (5-25 mg/kg, s.c.), induced a dose-dependent increase in locomotor activity that was prevented by pre-treatment with ketanserin (4mg/Kg i.p.) or haloperidol (0.25mg/Kg i.p.). Methylone was the most potent compound inhibiting both [3H]5-HT and [3H]DA uptake with IC50 values of 0.23±0.03 and 0.56±0.05 µM, n=3, respectively which correlate with its affinity for DA and 5-HT transporter (Ki values of 0.86±0.24 and 6.49±1.66 µM, respectively). Mephedrone showed the highest affinity for VMAT2-mediated DA uptake (IC50 value of 3.40±0.20 µM, n=3). The affinity of these cathinones for 5- HT2A receptors (measured as displacement of [3H]ketanserin binding) was similar to that of MDMA (Ki values of 37.49±6.41; 3.96±0.22 and 11.12±2.89 µM, n=3, for butylone, mephedrone and methylone, respectively). Moreover, the affinity of these compounds for the D2 receptors (measured as displacement of [3H]raclopride binding) was in the high micromolar range (Ki values of 57.09±11.46; 50.86±3.45 and 191.28±9.44 µM, n=3, for butylone, mephedrone and methylone, respectively).

Conclusions: Butylone and methylone induce hyperlocomotion through an activation of 5-HT2A receptors and an increase in extracellular DA. They inhibited 5-HT and DA uptake by competing with the substrate. The effect of methylone on 5-HT and DA uptake partially persists after withdrawal. Only mephedrone-induced hyperlocomotion is dependent on endogenous 5-HT. Vesicular content plays a key role in the effect of mephedrone, especially in the 5-HT uptake inhibition. Its potency inhibiting noradrenalin uptake, leads us to the hypothesis of a sympathetic effect of mephedrone.

This work was supported by grants from Ministerio de Ciencia e Innovación (SAF2010-15948); Plan Nacional sobre Drogas (2010/005) and Generalitat de Catalunya (SGR977).