TL neuro

January 2, 2017

Current Topics in Behavioral Neurosciences on Novel Psychoactive Substances

Filed under: 4-MMC/Mephedrone, Cannabimimetics, Cathinones, IVSA, MDPV, Methylone — mtaffe @ 2:08 pm

There is a new Current Topics in Behavioral Neuroscience book on New and Emerging Psychoactive Substances that has been organized by Michael H. Baumann, Ph.D., of the Intramural Research Program of the National Institute on Drub Abuse. This editorial effort resulted in 18 chapters on various topics of interest which are now available online.

Chapter 1: Madras, B. The Growing Problem of New Psychoactive Substances (NPS) [link]

Chapter 2: Glennon, R.A. and Dukat, M. Structure-Activity Relationships of Synthetic Cathinones [link]

Chapter 3: Simmler, L.D. and Liechti, M.E. Interactions of Cathinone NPS with Human Transporters and Receptors in Transfected Cells [link]

Chapter 4: Solis, E. Electrophysiological Actions of Synthetic Cathinones on Monoamine Transporters [link]

Chapter 5: Baumann, M.H., Bukhari, M.O., Lehner, K.R., Anizan, S., Rice, K.C., Concheiro, M. and Huestis, M.A. Neuropharmacology of 3,4-Methylenedioxypyrovalerone (MDPV), its Metabolites, and Related Analogs [link]

Chapter 6: Negus, S.S. and Banks, M.L. Decoding the Structure of Abuse Potential for New Psychoactive Substances: Structure-Activity Relationships for Abuse-Related Effects of 4-Substituted Methcathinone Analogs [link]

Chapter 7: Watterson, L.R. and Olive, M.F. Reinforcing Effects of Cathinone NPS in the Intravenous Drug Self-Administration Paradigm [link]

Chapter 8: Aarde, S.M. and Taffe, M.A. Predicting the Abuse Liability of Entactogen-Class, New and Emerging Psychoactive Substances via Preclinical Models of Drug Self-administration.[link]

Chapter 9: King, H.E. and Riley, A.L. The Affective Properties of Synthetic Cathinones: Role of Reward and Aversion in Their Abuse [link]

Chapter 10: Kiyatkin, E.A. and Ren, S.E. MDMA, Methylone, and MDPV: Drug-induced Brain Hyperthermia and its Modulation by Activity State and Environment [link]

Chapter 11: Angoa-Pérez, M., Anneken, J.H., Kuhn, D.M. Neurotoxicology of Synthetic Cathinone Analogs [link]

Chapter 12: Wiley, J.L, Marusich, J.A. and Thomas, B.F. Combination Chemistry: Structure–Activity Relationships of Novel Psychoactive Cannabinoids [link]

Chapter 13: Tai, S. and Fantegrossi, W.E. Pharmacological and Toxicological Effects of Synthetic Cannabinoids and Their Metabolites [link]

Chapter 14: Järbe, T.U.C. and Raghav, J.G. Tripping with Synthetic Cannabinoids (‘Spice’): Anecdotal and Experimental Observations in Animals and Man [link]

Chapter 15:Halberstadt, A.L. Pharmacology and Toxicology of N-Benzylphenethylamine (“NBOMe”) Hallucinogens [link]

Chapter 16: Papaseit, E., Molto, J., Muga, R., Torrens, M., de la Torre, R. and Farre, M. Clinical Pharmacology of the Synthetic
Cathinone Mephedrone [link]

Chapter 17: Mayer, F.P., Luf, A., Nagy, C., Holy, M., Schmid, R., Freissmuth, M., Sitte, H.H. Application of a Combined Approach to Identify New Psychoactive Street Drugs and Decipher Their Mechanisms at Monoamine Transporters [link]

Chapter 18: Schifano, F., Orsolini, L., Papanti, D., Corkery, J. NPS: Medical Consequences Associated with Their Intake [link]

 

December 3, 2016

New Chapter on Entactogen Self-Administration

Filed under: 4-MMC/Mephedrone, alpha-PVP, Cathinones, MDPV, Methylone — mtaffe @ 2:48 pm

We have recently published a short review on the self-administration of entactogen psychostimulants.

Aarde, S.M. and Taffe, M.A. Predicting the Abuse Liability of Entactogen-Class, New and Emerging Psychoactive Substances via Preclinical Models of Drug Self-administration. Curr Top Behav Neurosci. 2016 Dec 2. [Epub ahead of print] [PubMed][Publisher Site]

This is part of a Current Topics in Behavioral Neuroscience book on New and Emerging Psychoactive Substances organized by Mike Baumann of the NIDA IRP who has been publishing a lot of work on synthetic cathinones lately. Eventually the Chapters will be collected into a book and assigned unique pagination.

For now you can look chronologically in the pre-publication OnlineFirst list.

The first chapter of the series that was published was:
Schifano et al “NPS: Medical Consequences Associated with Their Intake” [link]

The cannabinoids are covered:
Wiley, Marusich and Thomas Combination Chemistry: Structure–Activity Relationships of Novel Psychoactive Cannabinoids [link]

All told there will be around a dozen chapters, I think most of them are on the pre-print list already. Happy reading!

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.

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*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.

September 1, 2015

MDPV and Methylone self-administration in rats

Filed under: Cathinones, Methylone — mtaffe @ 1:19 pm

A new paper from the Designer Drugs Research Unit within the NIDA IRP compares the self-administration of MDPV and methylone in rats. Methylone (3,4-methylenedioxymethcathinone) appears to have replaced MDMA in the NFLIS forensic laboratory database 2013-2014. This is only the third group to publish self-administration data with methylone so this is a very welcome tie-breaker. Watterson and colleagues (2012) reported fairly robust self-administration of methylone in male Sprague-Dawley rats and we reported marginal to weak self-administration in both female and male Wistar rats.

Schindler CW1, Thorndike EB, Goldberg SR, Lehner KR, Cozzi NV, Brandt SD, Baumann MH. Reinforcing and neurochemical effects of the “bath salts” constituents 3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) in male rats. Psychopharmacology (Berl). 2015 Aug 29. [Epub ahead of print] [ PubMed ]

Schindler15-Fig1IVSAIn this new study the authors trained male Sprague-Dawley rats to self-administer MDPV (0.03 mg/kg/infusion) or methylone (0.3 mg/kg/infusion) in two hour sessions during the dark (active) cycle. This figure to the right depicts nose-poke responses for the drug-associated (active) and non-associated (inactive) holes. Sessions indicated by A indicate Acquisition and E1-E6 indicate extinction sessions in which no drug resulted from a nose-poke response. Shaded symbols indicate when active and inactive responding was significantly different. The comparison makes it clear that while basic self-administration criteria were established for both drugs (active and inactive responding differed) the MDPV group made more responses than the methylone-trained group. They also exhibited a clear patter of self-administration from the second day of training compared with the seventh session for methylone. A followup study (Fig 2 of the paper) trained a group on a slightly higher 0.5 mg/kg/inf methylone dose (identical to the one we used and the highest, most effective dose used in the Watterson et al (2012) study). This group was given 17 acquisition sessions and the trajectory of behavior matched that of the 0.3 mg/kg group.

Schindler15-DoseResponse After acquisition, and before the extinction sessions reported in the first figure, the authors conducted a dose-substitution procedure in which the MDPV and 0.3 mg/kg/inf methylone [I didn’t mention the cocaine-trained group in the above discussion, but they were included in the study.] animals were given varying doses of drug in each infusion on different days. Each dose was provided on three consecutive days and the intakes on days 2-3 are reported here. As you can see, the methylone trained animals were insensitive to dose-substitution, particularly in comparison with MDPV (or cocaine) trained rats. This is very similar to our finding, particularly if you consider that the Schindler paper didn’t use a dose of methylone higher than 0.5 mg/kg/infusion in their procedure. In Vandewater et al (2015) and in Creehan et al (2015) the methylone-trained male and female rats really only expressed differences in intake between 0.125 and 2.5 mg/kg/inf doses. The functions were pretty linear (and descending, like the cocaine one shown above) but they were very shallow.

The take-away message is pretty similar to our studies and discordant with the findings of Watterson, et al 2012, 2014. Methylone supports low levels of self-administration in rats, but to a much lower extent than does MDPV in a direct comparison here. A similar indirect comparison of our studies (Vandewater et al 2015; Creehan et al 2015 vs Aarde et al, 2013, Aarde et al, 2015) comes to the same conclusion.

August 19, 2015

Mephedrone is also more reinforcing than MDMA or Methylone in male rats

Filed under: 4-MMC/Mephedrone, Cathinones, MDMA, Methylone — mtaffe @ 2:30 pm

StructureFig-MDMA-Methylone-MephedroneMethylone has now surpassed MDMA in Forensic Laboratory samples in the US. Mephedrone is less popular in the US but maintains a high degree of popularity in the UK. We recently published a paper [Creehan et al, 2015; PubMed; blogpost] showing that the drug mephedrone was a more effective reinforcer than either MDMA or methylone in female rats.

Our followup study which compared the self-administration of these three drugs in male rats has been accepted for publication.

Vandewater, S.A., Creehan, K.M. and Taffe, M.A. Intravenous self-administration of entactogen-class stimulants in male rats. Neuropharmacology, 2015, 99:538-545. [ PubMed ][ Publisher Site ]

We are interested in the reinforcing potential of mephedrone and methylone due in large part to their neuropharmacological similarity to MDMA. Specifically, these three drugs have a relatively greater enhancement of serotonin in the nucleus accumbens of the rat brain compared with the enhancement of dopamine. The latter effect is associated with pleasurable/rewarding effects of traditional stimulant drugs like methamphetamine whereas the preferential serotonin release/accumulation is associated with reduced reward potential. In short, rats have shown much less intravenous self-administration of MDMA versus methamphetamine.

Fig1-XY-3drg-Acq The fact that Mephedrone and Methylone share the MDMA-like neurochemical profile groups them all together as atypical or entactogen-class stimulant drugs and predicts less compulsive use compared with traditional stimulants like methamphetamine. Yet several self-administration studies with mephedrone have already shown a greater abuse potential compared with MDMA. The one available study with methylone (Watterson et al, 2012; blogpost) prior to our work implied the same. Our study in female rats was the first to directly compare these three drugs and we confirmed that mephedrone is a much more effective reinforcer, thus predicting higher liability for compulsive use. MDMA and methylone, however, appeared to be quite similar.

Our new study in the male rats used essentially the same procedures as the study in females and had the same conclusion. In this figure we show mean (±SEM) daily infusions of drug (upper panel) and the proportion of responses on the drug-associated lever versus the inactive lever (lower panel) obtained for groups of male rats trained to self-administer MDMA (N=17), Methylone (N=14) or Mephedrone (N=15) in 2 hour sessions. [Significant differences from the first session within group are indicated by *, differences between mephedrone and both other groups by #, differences from methylone by ‡ and differences from MDMA by †.] The MDMA and mephedrone groups differed from each other and the methylone-trained group was intermediate.

The results from the female animals in the previous study differed slightly in that the methylone and MDMA intakes were nearly identical and were both significantly different from the mephedrone self-administration.

MDMA-Methylone-AcqWe did some follow up comparisons between males and females for the new paper and those ended up in the Supplemental Materials file. The only significant sex-difference was for the MDMA-trained groups where there was a significant main effect of rat sex confirmed in the analysis. The methylone intakes appeared to be nearly identical between males and females, as is depicted and the mephedrone intakes did not differ either (not shown).We did some further sub-groups analysis and found that this difference in MDMA self-administration was mostly in the less-preferring half of the male group.

At this point we have a direct confirmation of the enhanced liability of mephedrone for compulsive use over that of MDMA. This is a clear rejection of the suggestion based on intra-cranial self-stimulation reward data that it has reduced liability- clearly something is off about the way the results were interpreted by Bonano et al (2014). Methylone appears to be much more similar to MDMA although it might be a slightly more effective reinforcer in male rats. Nevertheless we still cannot reconcile our results with methylone self-administration with the apparently robust self-administration reported by Watterson et al (2012). As there are only now three published studies of the self-administration of methylone, we must await further studies to better understand the reasons for these different outcomes.

July 16, 2015

UPROXX theTRUTH: About Bath Salts

Filed under: 4-MMC/Mephedrone, alpha-PVP, Cathinones, MDPV, Methylone, Public Health — mtaffe @ 11:36 am

The UPROXX folks were kind enough to invite me to make a clip on the synthetic cathinones for their new ‘theTRUTH’ series.

This was a novel experience for me and it was very difficult. If you look closely at this video and the ones linked below, you will notice how many cuts there are. The production team basically wants you to spit out very short and pithy statements which they can edit together into a whole. So it was conducted in a sort of interview style with a producer asking me questions and me responding as briefly as possible. Often times the same point had to be made several times to get it right. I even had to record a series of hand gestures and transitional phrases in case they needed to bridge points!

After that it was in their hands to stitch it together and tell a story. Obviously, one of the things I was trying to do was to not say anything that could be edited into a context that misrepresented anything too badly. On the whole, I think the UPROXX production team did a good job, given the material (me) they had to work with.

Others in this theTRUTH series include pieces on Toxoplasma gondii and large earthquakes.

May 6, 2015

Methylone is replacing MDMA in Forensic Laboratory samples

Filed under: alpha-PVP, Cathinones, MDMA, MDPV, Methamphetamine, Methylone — mtaffe @ 10:38 am

The National Forensic Laboratory Information System (NFLIS) is, according to the Introduction to the 2014 Mid-year report [PDF]:

a program of the Drug Enforcement Administration (DEA), Office of Diversion Control NFLIS systematically collects results from drug analyses conducted by State and local forensic laboratories These laboratories analyze controlled and noncontrolled substances secured in law enforcement operations across the country, making NFLIS an important resource for monitoring illicit drug use

I was curious to see what this particular dataset had to say about the emergence of substituted cathinone stimulants such as mephedrone, methylone, MDPV and alpha-PVP. We work on the effects of these drugs and it is of interest to monitor the evolution of their use with various epidemiological measures. This is but one such measure and the relative penetration of a given drug may differ depending on whether the measure is from law enforcement, surveys of adolescents, online surveys, etc.

NFLIS-summaryThe NFLIS appears to have started systematically assessing several cathinone drugs in 2011. Either that or they were too infrequent to make the specific tables presented in the reports. These are relatively low incidence, you will note. For comparison, methamphetamine accounts for about 10% of reports and did not change much across 2010 to 2012 when MDMA reports dropped significantly. I would have predicted, before seeing these data, that the incidence of MDMA was still higher than these newer drugs. This figure shows that methylone is now more frequently reported in NFLIS samples than is MDMA. Methylone is probably the most MDMA-like of the cathinones in terms of structure (it is the direct cathinone cousin, 3,4-methylenedioxymethcathinone), neuropharmacology and subjective effects (to the extent this has been assessed).
The second surprise for me was seeing that MDPV and alpha-PVP are less commonly reported than methylone. I would have expected these drugs to have a higher representation, based on the emerging profile as traditional stimulants that support highly repetitive use.

h/t: Forensic Tox Guy

March 16, 2015

Overnight Wheel Access Decreases Stimulant Self-Administration

Filed under: Cathinones, Exercise, MDMA, Methamphetamine, Methylone — mtaffe @ 10:57 am

env046-325x325The following has recently been accepted for publicationpublished:

Shawn M Aarde, Michelle L Miller, Kevin M Creehan, Sophia A Vandewater, Michael A Taffe. One day access to a running wheel reduces self-administration of d-methamphetamine, MDMA and Methylone, 2015, Drug Alcohol Depend, 151:151-158. [Publisher Site, PubMed]

   The laboratory continues to study the role that exercise can play in altering stimulant drug self-administration using rodent models. Our initial paper found that if rats have concurrent access to intravenous methamphetamine and an activity wheel, the drug intake is suppressed below that of animals who can only access an immobile, locked wheel (Miller et al, 2012; blog). In that study, however, unlocking the wheel had no effect on the methamphetamine  intake for those animals who had self-administered methamphetamine for 7-14 sessions without wheel activity.

   A study by Smith and Witte (2012; PubMed) showed that if rats are provided wheel access in their home cages they will self-administer less cocaine. That study maintained constant conditions for groups of animals, thus it was not determined if home cage wheel access could overturn an established self-administration pattern.

   In this new study we examined the effects of overnight wheel access in the vivarium home cage on the intravenous self-administration of three different stimulant drugs in four different experiments. The key feature for our experiment was that animals were trained to stable levels of self-administration of methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA) or methylone in the absence of significant prior wheel experience or any ongoing wheel access.

Aarde15-22hrWheelFig2   This figure (click to enlarge) depicts the mean number of infusions earned by groups of rats trained to self-administer A) methamphetamine (1 hr sessions; 0.05 mg/kg/inf; N=18), B) methamphetamine (2 hr; 0.05 mg/kg/inf; N=13), C) MDMA (2 hr; 0.5 mg/kg/inf; N=11) or D) Methylone (2 hr; 0.5 mg/kg/inf; N=12). Data are presented for each of the first four days (Monday-Thursday) in a week in which animals had no access to the activity wheel in the home cage (No Wheel) or were permitted to use the wheels (Wheel; grey and open bars) following the first (M; Monday) session of the week. Therefore the critical comparisons are Monday sessions (no wheel access prior) with the subsequent three days within the Wheel week and between T, W and Th sessions across Wheel and No-Wheel weeks. In the figure, significant differences from the first session within a week are indicated by * and significant differences between Wheel-access and No-Wheel weeks by #.

   The design was repeated-measures meaning that each rat participated in all the conditions. We used a 2 cohort crossover design for the most part, meaning that each experiment was split into two groups of rats with one receiving the Wheel Access week first and the other cohort receiving the No Wheel week first. This order did not make any difference in the effect of the wheel so the data are presented by Wheel-Access condition without respect to the order in which a given rat received the different conditions.

   The key takeaway message for this study is that wheel access in the ~22 h prior to a behavioral session is capable of significantly reducing the amount of drug rats will self-administer.

   This effect was replicated across four studies which varied in specific design, therefore we can conclude it is robust against methodological variation.

Implications:
   First, this is a confirmation of something that was made obvious by the Smith and Witte (2012) paper. There have been several papers that purport to show that a 6 week history of wheel access in the home cage prior to the initiation of drug self-administration training reduces drug intake. To the extent such models continue the wheel access during the self-administration training, they are confounded with the effect we have shown here. Consequently, neurobiological studies predicated on brain changes that require extensive exercise histories, such as neurogenesis processes, are likely to come up with negative results.

   Second, this study shows that it is possible for an activity intervention to reduce drug self-administration after a pattern of daily intake has been stabilized. It may not occur in every design but it is possible. This supports the further use of this model to study the ways in which exercise programs for human users might be best designed and applied. It even suggests that exercise programs can reduce drug use even without the subject having any intention to alter their use pattern.

Future Directions:
   There are numerous avenues to pursue in the wake of this study. From the behavioral perspective, we are not certain where, in the course of 22 hr of wheel access, the effect on drug intake lies. It is possible that this effect depends on activity early in the dark cycle (rats are nocturnal so this is their active part of the day), just prior to the self-administration session. It is also possible that wheel activity immediately after the last day’s session while acutely intoxicated on the stimulant is somehow aversive and thereby punishes subsequent drug taking. From a mechanistic perspective, it is pretty clear that the most profitable avenue is to follow up on the acute effects of exercise that emerge within a time frame no longer than about 22 hrs. The endogenous opioid systems are particularly attractive becuase of decades-old understandings that the so-called “runner’s high” may be mediated by such neurochemical systems.

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activity wheel picture from Med Associates, Inc

January 9, 2015

Mephedrone is more reinforcing than methylone or MDMA in female rats

Filed under: 4-MMC/Mephedrone, Cathinones, IVSA, MDMA, Methylone — mtaffe @ 9:27 am

A paper from the laboratory on the self-administration of MDMA-like cathinone drugs has been recently accepted for publication published online.

Creehan, K.M., Vandewater, S.A. and Taffe, M.A. Intravenous self-administration of mephedrone, methylone and MDMA in female rats. Neuropharmacology, 2015, 92:90-97. DOI: 10.1016/j.neuropharm.2015.01.003 [Publisher Link, PubMed]

 

This paper is the result of our “Open Experiment in Open Experimenting” which is chronicled on the linked page.
StructureFig-MDMA-Methylone-MephedroneBackground 1: Cathinones, aka “bathsalts”
There are a number of synthetic cathinone stimulants that are in reasonably substantial and continued use in the US, as well as elsewhere worldwide. Cathinone, the core molecule differs from amphetamine in the addition of a ketone in the beta position. In the figure, 3,4-methylenedioxymethamphetamine (MDMA or “Ecstasy”) can be contrasted with its cathinone cousing Methylone, which might otherwise be called 3,4-methylenedioxymethcathinone. If you see Methylone referred to as “bk-MDMA”, as it sometimes is with users, you will now be able to recognize what “beta-keto-MDMA” means. Mephedrone more or less led the emergence of substituted cathinones with one death noted in Sweden in 2008 and a major increase in prevalence in the UK throughout 2009 and 2010. To my view there has never been a major place in the recreational pharmacopeia for 4-methylmethamphetamine, the amphetamine cousin of mephedrone.

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.

Background 3: Female animals
The NIH has recently issue a policy position which reinforces the critical importance of conducting sex-difference comparisons across biomedical domains (Clayton and Collins 2014). It has been shown that female rats will self-administer more cocaine (Roth and Carroll 2004b; Smith et al. 2011) and more methamphetamine (Reichel et al. 2012; Roth and Carroll 2004a) than males; these sex differences can be more pronounced under long-access escalation and/or Progressive Ratio procedures. Little is known about any possible sex differences in the self-administration of atypical stimulants like MDMA or the recently emerging MDMA-like designer cathinones. In short, we couldn’t find a single report of IVSA of any of these compounds in female rats (although Oakly et al, 2014 fails to specify the sex). Thus, the present study was conducted in female rats to expand understanding of the comparative reinforcing properties of these compounds.

 
Results
Creehan15-Fig2-infusionsThis figure from the paper (click to enlarge) illustrates the number of infusions of drug obtained by three groups of female Wistar rats during the acquisition phase of intravenous self-administration (IVSA). Each group was trained on a different drug. The take-away messages is in the upper panel. At equal training doses the rats trained on mephedrone (4-methylmethcathinone, 4-MMC) take more infusions across the training interval. [Significant difference from the first session within group by *, Between mephedrone and both other groups by #, versus methylone by ‡ and versus MDMA by †.].
The bottom two panels of the figure split the groups into the upper and lower halves based on average drug intake during the acquisition interval. The point of doing so is that the Schenk lab studies (here, here) have shown that ~40-50 percent of (male, normal or wild-type) rats will fail to meet their acquisition criteria for MDMA IVSA. This is unusual for stimulant IVSA- something like 80-100% would be more typical for cocaine. Instead of creating arbitrary “acquisition” criteria, we chose to report subgroup analyses (the paper also contains drug-associated lever discrimination ratio information). Mephedrone was still preferred by the lower-preference animals and we illuminated a small advantage for methylone IVSA in the more-preferring Upper Half compared with the MDMA trained animals.

Conclusions
This direct comparison paper verifies a picture which has been emerging with the nascent IVSA literature on mephedrone- i.e., that it is clearly more effective as a reinforcer compared with MDMA. This points back to the neuropharmacological effects outlined above (enhanced serotonin response in nucleus accumbens of rats) and raises new questions about the relevance of such properties in predicting abuse liability. Together, these behavioral findings oppose a claim advanced by Bonano and colleagues (2014) on the basis of intracranial self-stimulation reward data that mephedrone has decreased abuse liability relative to methylone and MDMA.

There is only the single other paper on methylone IVSA and our results do not concur with the findings of Watterson et al (2012). Obviously there are methodological differences so additional experiments will be needed to gain better clarity on the propensity of methylone to support IVSA compared with MDMA and mephedrone. There was a hint in our data that for the more-preferring animals methylone might be slightly superior to MDMA as a reinforcer. So it isn’t impossible that some methodological issues might uncover a larger methylone/MDMA difference.

 

Relevant Literature
Aarde SM, Huang PK, Creehan KM, Dickerson TJ, Taffe MA. The novel recreational drug 3,4-methylenedioxypyrovalerone (MDPV) is a potent psychomotor stimulant: self-administration and locomotor activity in rats. Neuropharmacology. 2013 Aug;71:130-40. doi: 10.1016/j.neuropharm.2013.04.003. Epub 2013 Apr 15. [PMC (free) Link]

Aarde SM, Angrish D, Barlow DJ, Wright MJ Jr, Vandewater SA, Creehan KM, Houseknecht KL, Dickerson TJ, Taffe MA. Mephedrone (4-methylmethcathinone) supports intravenous self-administration in Sprague-Dawley and Wistar rats. Addict Biol. 2013 Sep;18(5):786-99. doi: 10.1111/adb.12038. Epub 2013 Jan 30.[PMC (free) Link]

Clayton JA, Collins FS (2014) Policy: NIH to balance sex in cell and animal studies. Nature 509: 282-3

Hadlock GC, Webb KM, McFadden LM, Chu PW, Ellis JD, Allen SC, Andrenyak DM, Vieira-Brock PL, German CL, Conrad KM, Hoonakker AJ, Gibb JW, Wilkins DG, Hanson GR, & Fleckenstein AE (2011). 4-Methylmethcathinone (mephedrone): neuropharmacological effects of a designer stimulant of abuse. The Journal of pharmacology and experimental therapeutics, 339 (2), 530-6 PMID: 21810934

Motbey CP1, Clemens KJ, Apetz N, Winstock AR, Ramsey J, Li KM, Wyatt N, Callaghan PD, Bowen MT, Cornish JL, McGregor IS.High levels of intravenous mephedrone (4-methylmethcathinone) self-administration in rats: neural consequences and comparison with methamphetamine.J Psychopharmacol. 2013 Sep;27(9):823-36. doi: 10.1177/0269881113490325. Epub 2013 Jun 5.

Roth ME, Carroll ME (2004a) Sex differences in the acquisition of IV methamphetamine self-administration and subsequent maintenance under a progressive ratio schedule in rats. Psychopharmacology 172: 443-449

Roth ME, Carroll ME (2004b) Sex differences in the escalation of intravenous cocaine intake following long- or short-access to cocaine self-administration. Pharmacol Biochem Behav 78: 199-207

Watterson LR, Hood L, Sewalia K, Tomek SE, Yahn S, Johnson CT, Wegner S, Blough BE, Marusich JA, Olive MF (2012) The Reinforcing and Rewarding Effects of Methylone, a Synthetic Cathinone Commonly Found in “Bath Salts”. J Addict Res Ther S9:002: 1-8

September 17, 2013

Bathsalts involved in 22,904 Emergency Department Visits in the US in 2011

Filed under: 4-MMC/Mephedrone, Cathinones, MDMA, Methylone — mtaffe @ 12:09 pm

Newly released data from the Drug Abuse Warning Network under SAMHSA, detail Emergency Department visits that involved bathsalts in 2011 [PDF].

Samhsa-ER-bathsaltsSep2013Unfortunately I can’t find any definition of the terms so I don’t know if any specific drugs had to be confirmed in body tissues or not. Nor do I know what they lumped under this catchall street-name for their data collecting and analysis. At the very least we have to presume there is some diversity here in terms of the actual drug being used. Mephedrone, methylone and MDPV have to be the suspects based on apparent presence in the US but since medical emergency is presumably rare, it may be that these visits disproportionally represent some other drug. Presumably in the cathinone class…but perhaps not.

One thing that would be of interest, but not something that appears in this dataset, would be a review of symptoms. The presence of “bath salts” with other drug combinations can be interpreted several ways. For example, it could suggest that bathsalts are more of a problem in the presence of other drugs…but symptom discrimination could help. Lethal or near-lethal alcohol and stimulant profiles look very different so if you have an alcohol+bathsalts case that looks like stimulant overdose, the presumption has to be that the alcohol had little to do with it.

In other recent news, three “molly” related deaths over the recent months have been confirmed as involving methylone, MDMA and methylone with MDMA, respectively.

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