TL neuro

March 2, 2016

Escalation of mephedrone IVSA under long-access conditions

Filed under: 4-MMC/Mephedrone, Cathinones, Methylone — mtaffe @ 10:41 am

StructureFig-MDMA-Methylone-MephedroneWe continue to be interested in assessing the relative abuse liability of new synthetic cathinone stimulants that pop up in recreational users. The most established entities such as mephedrone (4-methylmethcathinone; 4-MMC) and methylone (3,4-methylenedioxymethcathinone) are of particular interest to our research because they share some pharmacological properties with MDMA (Ecstasy), constituting a class of stimulants sometimes called entactogens. As you can see from the structures at the left, methylone is the direct cathinone cousin of MDMA– the ketone group on the beta carbon is the element that differentiates a cathinone from an amphetamine.

The 2013 and 2014 NFLIS showed that methylone may be more common than MDMA in the US and mephedrone continues to be popular in the UK. Our recent papers (Vandewater et al, 2015 and Creehan et al, 2015) compared the intravenous self-administration (IVSA) of methylone, mephedrone and MDMA within relatively short (2 h) daily training sessions in male and female rats, respectively. We found that rats will IVSA greater amounts of mephedrone compared with MDMA with methylone falling in between the other two. One prior study had found that rats will IVSA methylone at very high rates, more like a traditional stimulant than like MDMA, thus we were curious to further examine potential differences.

It has been shown that relatively long (6 h) daily sessions of access to cocaine (Ahmed and Koob, 1998; Larson et al., 2007) or methamphetamine (Kitamura et al., 2006; Schwendt et al., 2009) IVSA results in both higher daily drug intake and a progressive increase across sessions (termed “escalation”) relative to animals trained only in 1-2 h sessions. This has been conceptualize as a better rat model of the state of human stimulant addiction, as opposed to the interpretation of mere drug liking. In contrast, a prior study found no difference in total session intake of the entactogen class stimulant MDMA between long (6 h) and short (2 h) access groups over the first 11 sessions (Schenk et al., 2003). This seemed a little unusual to us and we showed in Vandewater et al (2015) that when run in the dark cycle (the rats’ active period of the day), male rat IVSA of MDMA
Fig1-LgA-ShA-MethyloneMMC-Revunder 6 h daily access conditions is higher than under 2 h access conditions. So we conducted a new study to determine how the rat IVSA of the two entactogen (MDMA-like) cathinones would fare under 6 h access conditions. The following has been recently accepted for publication:

Nguyen, J.D., Grant, Y., Creehan, K.M., Vandewater, S.A. and Taffe, M.A. Escalation of intravenous self-administration of methylone and mephedrone under extended access conditions., Addict Biol, 2016, in press. [ Publisher Site ][ PubMed ]

This study was conducted in male rats, trained to intravenously self-administer methylone or mephedrone in Short Access (ShA; 2 h) or Long Access (LgA; 6 h) sessions. The training dose was 0.5 mg/kg per infusion for each drug. The mean (SEM) number of infusions obtained by the four different groups is depicted in the first figure from the paper, reproduced here. There are two takeaway messages. First, the total daily intake is higher for the LgA groups for both drugs. Secondly the mephedrone LgA group obtained more infusions than did the methylone LgA group. [Significant differences from the first three sessions within group are indicated by shaded symbols. Significant differences between Access groups within a drug are indicated by * and differences between drugs, within Access condition, by †.] This further confirms, as did our MDMA LgA study, that there is nothing weird about entactogen IVSA under LgA vs ShA conditions- rats take more drug in 6 h than in 2 h. It also emphasizes that rats will take more mephedrone than methylone.

First 2 h intake of LgA groups

First 2 h intake of LgA groups Significant differences from the first three sessions within group are indicated by shaded symbols. Significant differences from MDMA are indicated by * and from methylone by †.

In some senses that is a trivial observation and one of the key measures of rats having achieved a state more similar to the addicted human is whether the LgA animals gradually take more drug in the time interval commensurate with the ShA animals- in our case the initial two hours of their 6 h session. This graph depicts the first 2 h infusions for the mephedrone (4-MMC) and methylone trained animals from this new study as well as the similar data for the MDMA 6 h animals from* Vandewater et al (2015). As you can see in this graph, the three drugs are clearly distinguished from each other on this key measure of “escalated” drug seeking behavior. First 2 h intake of MDMA is relatively stable across this training interval, first 2 h methylone intake increases across sessions and first 2 h mephedrone intake increases even more. The conclusion we reach from this is that both methylone and mephedrone have enhanced abuse liability compared with MDMA and they are more likely to lead to patterns of relatively uncontrolled or compulsive drug use in humans.

We also took this new study one step farther by asking how hard the four groups would work for a given magnitude of drug infusion. We do this by using a Progressive Ratio procedure. In the normal training the animals have a Fixed Ratio (as it is called) of lever presses to infusions. In this study, it was FR1 meaning they had only to make one press on the drug-associated lever to get an infusion of drug. In the PR procedure, the number of responses required for each successive drug infusion is progressively increased throughout the session (e.g., 1, 2, 4, 8, 16….). Eventually the rats will stop obtaining drug infusions. The last ratio they completed for a drug infusion is called the “breakpoint”, indicating how many lever presses they made for that final infusion. We also varied the available drug dose per infusion in a random order across session. Thus, we obtain an estimate of how hard each group will work for a given dose of drug. In order to directly compare liability for stimulant drug seeking across the groups we used the same two test drugs, methamphetamine (MA) and mephedrone/4-MMC.

The top panels contrast breakpoints during methamphetamine (MA) substitution in A) ShA and B) LgA groups. The bottom panels contrast breakpoints reached during mephedrone (4-MMC) dose substitution in C) ShA and D) LgA groups. Significant differences from vehicle control within-group are indicated by *, from the 0.125 dose by # and from all other dose conditions by %. Significant differences from all other groups, within a dose condition, are indicated by †.

The top panels contrast breakpoints during methamphetamine (MA) substitution in A) ShA and B) LgA groups. The bottom panels contrast breakpoints reached during mephedrone (4-MMC) dose substitution in C) ShA and D) LgA groups. Significant differences from vehicle control within-group are indicated by *, from the 0.125 dose by # and from all other dose conditions by %. Significant differences from all other groups, within a dose condition, are indicated by †.

This direct comparison study found that the rats trained to IVSA mephedrone under LgA conditions worked harder for either their training drug mephedrone or MA than did any other the other groups. There was no similar LgA/ShA difference for methylone-trained rats. This further emphasizes the substantial abuse liability of mephedrone/4-MMC. This drug appears to be quite similar to classical stimulants like methamphetamine and cocaine in this respect.

It continues, therefore, to be a mystery why a drug which releases serotonin in the nucleus accumbens to a greater degree than it releases dopamine would be such an effective reinforcer in the rat IVSA assay. There is considerable evidence, beyond just the fact that rats are pretty reluctant to IVSA MDMA compared with methamphetamine, that increasing serotonergic over dopaminergic effects of drugs is going to decrease the effectiveness as a reinforcer. And therefore decrease the liability for repeated use patterns. One of the scientific benefits of looking into the rewarding properties of some of these new cathinone stimulants is precisely this. It can suggest places where the existing dogma, based on the amphetamines in large part, may need some reconsideration.

__
*We originally submitted this paper including a comparison with the prior MDMA group, cited and referenced so that there was no confusion as to where the data came from. First, a reviewer mentioned that this may be inappropriate. Second, the handling Editor noted that this was against journal policy. After a bit of back and forth with the Editor over the reasons for making this comparison we had to cave and remove the direct (i.e. including statistical comparisons) contrast with those prior data.

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