TL neuro

July 15, 2013

Mephedrone and MDPV share discriminative stimulus effects with Cocaine and Methamphetamine

Filed under: 4-MMC/Mephedrone, Cathinones, MDPV, Methylone — mtaffe @ 12:50 pm

A new paper by Gatch [Dept Website] and colleagues describes the locomotor stimulant and discriminative stimulus effects of several cathinone derivatives in mice and rats respectively.

Gatch MB, Taylor CM, Forster MJ. Locomotor stimulant and discriminative stimulus effects of ‘bath salt’ cathinones. Behav Pharmacol. 2013 Jul 8. [Epub ahead of print][PubMed, DOI]

The paper examines the locomotor stimulant effects of MDPV, mephedrone, methylone (bk-MDMA), flephedrone, naphyrone and butylone in mice. Additional comparisons are made with methamphetamine and cocaine. All of the compounds, except cocaine, tested illustrated a typical inverted-U dose-response function in which low doses are ineffective, moderate doses cause a peak in locomotor activity and at the highest dose activity is either no different than the vehicle condition or actually suppressed. Although we didn’t observe any high-dose suppression of activity with mephedrone in our rat studies, this is probably because we didn’t extend to a high enough dose. This is probably the reason Gatch and colleagues only reported increased locomotor activity with cocaine. Of greatest interest to the authors was the finding that the highest doses of MDPV and naphyrone caused locomotor stimulation in the mice that lasted for 6-8 hrs, slightly longer than did the effect of the highest dose of methamphetamine tested.

Of perhaps greater interest are the drug-discrimination data. In this assay, the rat is trained to respond on one of two levers (typically) for food pellet rewards. The key feature is that the animal is injected prior to the session with either a training drug or the inactive vehicle (saline, typically). Then, for that session only responses on one of the levers is rewarded with a food pellet. So the animals are trained to response on one lever when they feel the training drug and the other lever when they feel saline. Once they are trained above 80% correct responding in each condition then the experimenter can start substituting other drugs in place of the training drug. If the rats respond more than 80% on the drug-associated lever at some dose of the new test compound then it is said to substitute for the training drug. In essence to report whether it “feels like” the original drug.

Gatch13-Fig4Although I won’t go into it here, the history of such work is extensive and at least across classes of drugs, the rats will generally fail to report an opiate drug (like heroin, say) to be like cocaine. The results are reasonably selective to drug-class. In Figure 4 of the paper, reproduced here, it is shown that at least one dose of MDPV, methylone, mephedrone (4MMC), Naphyrone, Flephedrone and butylone will lead to 80% or more responding on the lever that had been paired with the training dose of cocaine. You can also see that if the training dose of cocaine is lowered, animals are decreasingly likely to respond on the drug-paired lever.

Gatch13-Fig5In the next figure the same drugs are examined in a group of animals trained to discriminate methamphetamine from saline. Again, all of the cathinones fully substituted for the training drug. You will note that there is some variation in the precise dose at which the methamphetamine-trained animals reported drug-like effects versus the dose for the cocaine-trained animals. The authors then went on to run correlations of the ED50 values (the calculated dose at which 50% drug-appropriate responding would occur based on these curves) with pharmacological properties reported by Eshleman et al, (2013). Gatch and colleagues reported that the potency (ED50) of these compounds in the cocaine-trained animals correlated only with their potency to activate serotonin 1A receptors and in the methamphetamine-trained animals with the cathinone’s potency to release norepinephrine via the vesicular monoamine transporter 2 (VMAT-2). This latter is an intracellular target of the prototypical amphetamines and relates to their neurotransmitter “releasing” (as opposed to merely re-uptake blocking) effect. Curiously, the potency of these drugs to substitute for cocaine was not correlated with the potency to substitute for methamphetamine.

It is worth reminding at this point that these correlative findings (all other properties did not correlate with the differences in potency) do not necessarily identify the major neuropharmacological action of these drugs that make them feel like cocaine and methamphetamine, respectively. These findings identify the reasons for what are subtle differences in the potency of the test drugs. Thus the effect at the serotonin 1A receptor subtype and the VMAT-2 for norepinephrine release must be viewed as modulatory effects. The authors suggest that once a certain threshold for changed monoamine levels is reached, the discrimination assay is insensitive. They overlook, however, the consideration that a multi-factor model might need to be considered. That is, potency might be driven by the precise combination of effects on dopamine, serotonin and norepinephrine transporters as further modified by such considerations as the speed of drug passage into the brain across the blood-brain barrier, speed of metabolism of the drug, any active metabolites, etc.

One of the interesting thing about this paper is perhaps that it highlight the limitations of the drug-discrimination paradigm for making close distinctions within a given drug class such as the psychomotor stimulants. The pharmacological studies being published in recent months are showing pretty clearly that some of the cathinones (MDPV, butylone, naphyrone) are limited to monoamine uptake inhibition like cocaine whereas the others also exhibit the amphetamine-typical monoamine releasing capability. Likewise, the studies show a diversity of potencies at the dopamine, serotonin and noradrenergic transporters and in causing dopamine versus serotonin overflow in nucleus accumbens.

We’ve now shown potency and efficacy differences in drug self-administration for MDPV and mephedrone versus methamphetamine. Likewise, rat activity on a running wheel classifies MDPV and methamphetamine as prototypical stimulants with similar potency compared with mephedrone and MDMA.

Considered as a whole, the behavioral studies should be interpreted with caution in that each comparison with a better known stimulant drug, or each comparison across the cathionone class, depends on the model or measure. Clearly, some behavioral assays will report two different drugs as very similar in effect whereas another might illustrate differences, particularly in potency or the maximum extent of the effect.

Nevertheless, it is also very clear that at least some members of the novel designer cathinone family of recreational drugs have very potent and effective stimulant-like actions.

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