Mephedrone, compared with MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and 5-HT levels in nucleus accumbens of awake rats
J Kehr, F Ichinose, S Yoshitake, M Goiny, T Sievertsson, F Nyberg, T Yoshitake
Br J Pharmacol. 2011 December; 164(8 ): 1949–1958. doi: 10.1111/j.1476-5381.2011.01499.x
Dopamine and serotonin were collected using microdialysis, and increases in dopamine and serotonin were measured using HPLC. Reward and drug seeking are linked to increases in dopamine concentrations in the nucleus accumbens, and drug half-life plays a role in drug seeking as well. Based on histological examination, most of the author's probes were in the nucleus accumbens shell. Mephedrone administration caused a ~500% increase in dopamine, and a ~950% increase in serotonin. They reached their peak concentrations at 40 minutes and 20 minutes, respectively, and returned to baseline by 120 minutes post injection. In comparison, MDMA caused a ~900% increase in serotonin at 40 minutes, with a non-significant increase in dopamine. Amphetamine administration resulted in a ~400% increase in dopamine peaking at 40 minutes, with a non-significant increase in serotonin. Analysis of the ratio of the AUC for dopamine (DA) and serotonin (5-HT) indicated that mephedrone was preferentially a serotonin releaser, with a ratio of 1.22:1 (serotonin vs. dopamine). Additionally, half-lives for the decrease in DA and 5-HT were calculated for each drug. Mephedrone had decay rates of 24.5 minutes and 25.5 minutes, respectively. MDMA had decay values of 302.5 minutes and 47.9 minutes, respectively, while amphetamine values were 51 minutes and 84.1 minutes, respectively. Taken together, these findings show that mephedrone induces a massive increase in both DA and 5-HT, combined with rapid clearance. The rapid rise and subsequent fall of DA levels could explain some of the addictive properties that mephedrone displays in some users.
The toxicology of bath salts: a review of synthetic cathinones.
Prosser JM, Nelson LS.
J Med Toxicol. 2012 Mar;8 (1):33-42.
Cathinone is a naturally occurring beta-ketone amphetamine analogue found in the leaves of the Catha edulis plant. Synthetic cathinones are derivatives of this compound. Those that are being used as drugs of abuse include butylone, dimethylcathinone, ethcathinone, ethylone, 3- and 4-fluoromethcathinone, mephedrone, methedrone, methylenedioxypyrovalerone (MDPV), methylone, and pyrovalerone. Synthetic cathinones are phenylalkylamines derivatives, and are often termed "bk-amphetamines" for the beta-ketone moiety. They may possess both amphetamine-like properties and the ability to modulate serotonin, causing distinct psychoactive effects. Desired effects reported by users of synthetic cathinones include increased energy, empathy, openness, and increased libido. Cardiac, psychiatric, and neurological signs and symptoms are the most common adverse effects reported in synthetic cathinone users who require medical care. Deaths associated with use of these compounds have been reported. Exposure to and use of synthetic cathinones are becoming increasingly popular despite a lack of scientific research and understanding of the potential harms of these substances. The clinical similarities to amphetamines and MDMA specifically are predictable based on the chemical structure of this class of agents.
1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) analogues: a promising class of monoamine uptake inhibitors.
Meltzer PC, Butler D, Deschamps JR, Madras BK.
J Med Chem. 2006 Feb 23;49(4):1420-32.
Dopamine, serotonin, and norepinephrine are essential for neurotransmission in the mammalian system. These three neurotransmitters have been the focus of considerable research because the modulation of their production and their interaction at monoamine receptors has profound effects upon a multitude of pharmacological outcomes. Our interest has focused on neurotransmitter reuptake mechanisms in a search for medications for cocaine abuse. Herein we describe the synthesis and biological evaluation of an array of 2-aminopentanophenones. This array has yielded selective inhibitors of the dopamine and norepinephrine transporters with little effect upon serotonin trafficking.
Comparative neuropharmacology of three psychostimulant cathinone derivatives: butylone, mephedrone and methylone.
López-Arnau R, Martínez-Clemente J, Pubill D, Escubedo E, Camarasa J.
Br J Pharmacol. 2012 Apr 18. doi: 10.1111/j.1476-5381.2012.01998.x. [Epub ahead of print]
Locomotor activity was recorded in mice following different doses of cathinones. Monoamine uptake assays were performed in rat purified synaptosomes. Radioligand binding assays were carried out to assess the affinity of these compounds for monoamine transporters or receptors. Key results: Butylone, mephedrone and methylone (5-25 mg Kg(-1) ) caused hyperlocomotion which was prevented with ketanserin or haloperidol. Methylone was the most potent compound inhibiting both [(3) H]5-HT and [(3) H]DA uptake with IC(50 ) values that correlate with its affinity for DA and 5-HT transporter. Mephedrone was found to be the cathinone derivative with most affinity for VMAT-2 causing the inhibition of DA uptake. The affinity of cathinones for 5-HT(2A) receptors was similar to that of MDMA. [...] 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 NA uptake, leads us to the hypothesis of a sympathetic effect of this cathinone.
Cozzi, N.V., Sievert, M.K., Shulgin, A.T., Jacobill, P. and Ruoho, A.E. (1999) Inhibition of plasma membrane monoamine transporters by beta-ketoamphetamines. European Journal of Pharmacology. 381: 63-69.
ACMD report on cathinones
Mephedrone report
To the best of my knowledge -
MDPV is a norepinephrine-dopamine reuptake inhibitor with little releasing efficacy.
4-MMC is a serotonin, norepinephrine, dopamine releaser and reuptake inhibitor, comparable to MDMA/amphetamine/methcathinone.
4-MEC would be expected to be more weighted towards norepinephrine release (compare methcathinone to ethcathinone).
The cathinones would also share affinity for random serotonergic (5-HT2A/B/C) and adrenergic receptors (alpha/beta) as well.
