TL neuro

May 10, 2013

Cathinones contradict easy structure-activity conclusions

Filed under: 4-MMC/Mephedrone, Cathinones, MDPV, Methylone — mtaffe @ 2:55 pm

As Wikipedia puts it regarding structure-activity relationships (SAR):

The basic assumption for all molecule-based hypotheses is that similar molecules have similar activities. This principle is the basis of a SAR. The underlying problem is therefore how to define a small difference on a molecular level, since each kind of activity, e.g. reaction ability, biotransformation ability, solubility, target activity, and so on, might depend on another difference….The SAR paradox refers to the fact that it is not the case that all similar molecules have similar activities.

We are in the midst of a rapid diversification of the identity of psychoactive molecules contained in recreational drug products sold as “bath salts”, “research chemicals” and other monikers. Per a recent Twitter comment just this morning from analytical chemist K.Shanks (see this paper):

First confirmed blood positive for 3,4-DMMC. Cool! Also had MDPV present.

Yes, very exciting times for those of us interested in the abuse, and effects, of stimulant drugs. The list of substituted cathinone drugs that have appeared in recreational products is lengthy and there are many additional possible modifications which will very likely appear in the future. It is very tempting to make strong inferences about likely effects of these drugs based on their molecular similarity to better-known drugs. Indeed, in the earlier days when 4-methylmethcathinone was the largest player in the UK, and as 3,4-methylenedioxypyrovalerone (MDPV) emerged in the US, there was initially very little specific information to draw upon. Our laboratory and others (see prior posts) have been working on characterizing the effects of cathinone derivative drugs and the papers are just starting to emerge. Simmler et al (2013) and Baumann et al (2012; 2013) are particularly good reads to get up to speed.

MDMA-methyloneA new paper from the M. Foster Olive laboratory (Watterson et al, 2012) examines the abuse liability of methylone in rodent self-administration models comparable to their prior study on MDPV. Methylone (3,4-methylenedioxymethcathinone) is the cathinone analog of MDMA (3,4-methylenedioxymethamphetamine) and is sometimes termed beta-keto-MDMA (or bk-MDMA) to denote the cathinone-characteristic modification of the amphetamine core. It looks very much like MDMA and produces MDMA-like (but not methamphetamine-like) effects on serotonin and dopamine accumulation in the nucleus accumbens. MDMA and methylone are distinguished by a relatively larger effect on serotonin accumulation versus dopamine accumulation. The latter is a signature effect of stimulant drugs and is correlated with abuse liability. In addition Dal Cason and colleagues showed in 1997 that methylone was reported as MDMA-like at a lower dose than it was reported as amphetamine-like in rats using a drug-discrimination procedure.

Figure 1: Intravenous self-administration (IVSA) of methylone. Data presented are active and inactive lever presses across the first 21 days of IVSA sessions for the (a) 0.05 (b) 0.1 (c) 0.2 and (d) 0.5 mg/kg/infusion groups (n = 12 for 0.05 and 0.5 mg/kg/infusion groups; n = 11 for the 0.1 and 0.2 mg/kg/infusion groups). *p<0.05 between active and inactive lever presses.

As you can see from the first figure, groups of rats increase their drug-associated lever pressing over 20 sessions across a dose range of 0.1-05 mg/kg per infusion. Pressing on the other lever remains low and constant, thus the animals are clearly seeking to self-administer the methylone. The amount of lever responding and the corresponding number of infusions of drug were about equivalent to what they found for the lowest per-infusion dose of MDPV (0.05 mg/kg/inf) in their prior study. Thus, methylone is a very effective (and potent) reinforcer in the rodent intravenous self-administration model of drug “liking”. From this perspective it looks like a traditional psychomotor stimulant compound and not as much like MDMA (which is not as readily self-administered by rats).

We have previously shown that mephedrone (4-methylmethcathinone; 4-MMC) is readily self-administered by rats despite an MDMA-like effect on body temperature and serotonin/dopamine accumulation in the nucleus accumbens as well as running wheel activity.

Clues as to why methylone might support self-administration can be found in Simmler et al (2013). That paper reports that methylone exhibits dopamine transporter / serotonin transporter inhibition potency ratios more similar to cocaine than to MDMA. The potency at the dopamine transporter alone is low, however, which may explain both the Baumann et al (2012) findings (which used only two doses) in comparison with the self-administration findings of Watterson and colleagues (2012). Since the self-administration paradigm is self-dosing, the animal can compensate for low potency by taking more drug. It has also been shown by Simmler and colleagues that methylone is a poor releaser of dopamine or serotonin, unlike the classical amphetamines and MDMA. Cocaine and MDPV share this property of inhibiting the transporters without also having any additional releasing effect. This has the potential to drive more frequent dosing, relative to a classical amphetamine.
Watterson LR, Hood L, Sewalia K, Tomek SE, Yahn S, et al. (2012) The Reinforcing and Rewarding Effects of Methylone, a Synthetic Cathinone Commonly Found in “Bath Salts”. J Addict Res Ther S9:002. doi: 10.4172/2155-6105.S9-002

UPDATE: I was wondering why this paper wasn’t in PubMed, according to this piece in Science, they are not accepting submissions from OMICS journals. FWIW.


1 Comment »

  1. […] Background 2: Empathogenic or MDMA-like neuropharmacology We have described in prior posts how mephedrone exhibits an MDMA-like trait of preferentially increasing serotonin versus dopamine overflow in the nucleus accumbens of rats; this is different from the dopamine-dominant response to methamphetamine or amphetamine. This pattern has been proposed to be intimately related to the fact that MDMA is only an uncertain reinforcer in rodent IVSA compared with the more typical amphetamines. Mephedrone is much more readily self-administered than MDMA and a single prior report seemed to indict that methylone likewise is an effective reinforcer in IVSA. […]

    Pingback by Mephedrone is more reinforcing than methylone or MDMA in female rats | TL neuro — January 9, 2015 @ 9:27 am

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