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]


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.

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.

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

November 11, 2014

MDPV self-administration devalues wheel activity

Filed under: Cathinones, Exercise, IVSA, MDPV — mtaffe @ 10:35 am

We’ve been interested in the way in which physical exercise can modulate the self-administration of stimulant drugs for quite some time now. The lead paper which sparks our interest is the Cosgrove et al 2002 which showed that when rats are permitted simultaneous access to a lever that delivers an intravenous infusion of cocaine and an activity wheel, the rates of each activity are mutually suppressed. This led to our Miller et al 2012 [Free PMC version; blog writeup] paper which showed that methamphetamine self-administration was reduced in rats when they had simultaneous access to an activity wheel during the self-administration session.

The following has been recently accepted for publication published online (prior to print):

Aarde, S.M., Huang, P-K, Dickerson, T.J. and Taffe, M.A. Binge-like Acquisition of 3,4-methylenedioxypyrovalerone (MDPV) self-administration and wheel activity in rats. Psychopharmacology, 2015, in press DOI: 10.1007/s00213-014-3819-4 [Publisher Site; PubMed]

In this paper we examine the effect of simultaneous wheel access on the self-administration of the cathinone stimulant MDPV [related blog posts]. For those having trouble picturing the methods, this product from Med Associates gives you the idea (the standard operant stuff goes to the left in the linked depiction).

Aarde15-BingeMDPVFig1-editedThis abbreviated first figure (click to enlarge) from the manuscript illustrates a difference from our Miller et al 2012 investigation. First, we did not train the rats beforehand to press the lever for food, thus this is an acquisition study in which the mean number of MDPV infusions (top panel) gradually increase with successive training sessions. This is unlike the methamphetamine study in which the number of infusions obtained during self-administration was reasonably steady from the start. This is because, presumably, animals did not have to learn to connect up lever pressing with the good feeling that resulted from drug infusion. In this study, however, the group that had the wheel access and the group that had no wheel access (actually they could walk on it, it was just fixed in place) did not differ in their MDPV self-administration. The similarity with the prior methamphetamine study lies in the gradual reduction in wheel activity that developed (lower panel). This we interpret (in both papers) as reflecting the supplanting of one source of reward (wheel activity) by another source (intravenous stimulant drug infusions).

What we were able to detect in this current design (but not the previous one) was that this is a single-session phenomenon. This figure is a modification of Figure 3 from the manuscript and illustrates the MDPV infusions of six individual subjects across a 20 session training interval.
Aarde15-BingeMDPVFig3-editedThe three individual subjects in the upper part of this second figure had their wheel fixed in place while the three in the lower panel were able to run (open symbols depict quarter wheel-rotations, QWR). Out of the total of 13 animals in the Unlocked wheel condition, six exhibited the pattern illustrated here wherein wheel activity declined simultaneously with an increase to sustained high MDPV self-administration. An additional 2 of the subjects exhibited a more gradual reduction in activity as MDPV self-administration increased. Thus, for almost half of the subjects examined, the drug/wheel supplanting was a single-session phenomenon. We go on to show in the paper that this actually took place on the scale of minutes within the critical sessions. We further more demonstrated that some of the animals were taking MDPV infusions during the binges as fast as they were able, given the time-out interval the methods imposed between each successive infusion of drug.

The figure above also illustrates another curious finding which was the spike in MDPV self-administration that appeared to initiate the individual starting point for a sustained pattern of drug taking. We have been unable to locate more than hints of this type of spontaneous binge-like initiation of intravenous self-administration of stimulant (or other) drugs. A defined spike of this nature was detected in about half of the subjects in the Locked Wheel and Unlocked Wheel training groups so it did not appear to be strongly affected by concurrent wheel access. Interestingly, this binge had consequences.

Aarde15-MDPVbingeFig5-editedIn this adaptation of Figure 5 from the manuscript, we show the mean number of MDPV infusions obtained (left panel) by the rats exhibiting the binge-like spike and those that did not (across the wheel access condition groups) both before and after “acquisition” which was defined as sustained intake of 6 or more infusions. The mean post-acquisition MDPV intake per session was signficantly higher in those animals who expressed a single-session spontaneous binge. The right panel shows that for the group that had Unlocked Wheels, the binge-like pattern (N=7) was associated with post-acquisition reductions in wheel activity whereas the non-binge acquisition pattern (N=6) resulted in no change in wheel activity.

Our conclusions from this study are threefold.
First, we further illustrate that MDPV is a highly effective reinforcer in rat self-administration models. Thus, this bath salt cathinone is predicted to have very high propensity for compulsive use in humans who sample it repeatedly.

Second, we show that under these conditions, the supplanting of wheel-activity reward for drug reward can be a very rapid, single session phenomenon in as many as half of the individuals tested. Therefore the appearance of a gradual shift from wheel to drug that appears in group mean data is an artifact of the individuals reaching the transition point at different amounts of experience.

Finally, we identify a binge-like pattern that heralds the start of sustained drug taking for about half of the individuals evaluated. This pattern is correlated with a higher level of sustained drug intake post-acquisition. We are uncertain at this point if this binge-like pattern causes this difference in sustained drug intake or if it merely serves as a marker of those highly-preferring individuals who are destined to prefer higher MDPV intakes. We also do not know if this is a unique property of MDPV self-administration of if it would be observed with other stimulant drugs under the right testing conditions.

April 4, 2013

3,4-methylenedioxypyrovalerone (MDPV, “bath salts”): A potent reinforcer with significant abuse liability

Filed under: Cathinones, IVSA, MDPV — mtaffe @ 11:46 am

The following paper has been accepted for publication:

Aarde, S.M., Huang, P-K, Creehan, K.M., Dickerson, T.J. and Taffe, M.A. The novel recreational drug 3,4-methylenedioxypyrovalerone (MDPV) is a potent psychomotor stimulant: self-administration and locomotor activity in rats. Neuropharmacology, 2013, 71:130-140. [ PubMed ][ PublisherSite ]

In this paper we contrast the novel substituted cathinone drug MDPV (apparently the most common “bath salt” in the US to date) with the better-known drug of abuse, d-methamphetamine (MA). For these studies we examined intravenous self-administration in male Wistar rats which were previously trained to complete a Fixed Ratio of 5 presses to obtain a food pellet reward. After exhibiting stable response rates for food, groups were switched to intravenous delivery of MDPV or MA (0.05 mg/kg/inf for either drug) as the reinforcer.

We show that rats will maintain stable levels of responding for drug within 10 sessions and that approximately twice as many infusion of MDPV are self-administered compared with MA under these conditions. We then went on to do a dose-substitution manipulation in which the available per-infusion dose was varied across sessions, first under FR5 conditions and then using a Progressive Ratio (PR) procedure.

Aarde13-MDPV-PR2In a PR approach, each successive reinforcer within the session requires more lever pressing to obtain than did the prior one. The idea is that as the amount of “work” required for each dose goes up, the animal will eventually quit responding. In this figure, reproduced from the paper, it is shown that the amount of pressing depends on dose and that rats will emit far more lever presses for MDPV than for MA. The ascending/descending curves were approximately superimposed in terms of the per-infusion dose for both compounds, this is typically interpreted as the drugs having similar potency. The relatively greater amount of lever responding (and therefore infusions obtained) is typically interpreted as greater efficacy of MDPV relative to MA. The only prior study of MDPV self-administration in a rat model (Watterson et al, in press) only compared one dose of MA to a narrower range of MDPV doses so it was not possible to make an extensive comparison from that study.

The paper also compared the locomotor and body temperature effects of acute bolus challenge with MDPV and MA. We found a similar propensity of MDPV and MA to increase home cage locomotion with a stimulant-typical inverted-U dose-response function (1.0 mg/kg, s.c. most effective for both drugs). This finding was similar to our prior report on exercise wheel activity (Huang et al, 2012). We found very little modulation of body temperature after MDPV administration; this lack of effect contrasts with hyperthermia reported in a mouse model by Fantegrossi and colleagues. Additional work will be required to understand if this is a matter of the doses used, the species in question or possibly the ambient temperature under which the studies were conducted.

Finally, we show that MDPV induces repetitive, stereotyped behavior in a dose-dependent manner under both acute-challenge and self-administration conditions.

The paper demonstrates that MDPV is a prototypical psychomotor stimulant. It is potently reinforcing in a self-administration model of compulsive use, stimulates locomotor activity at moderate doses and induces repetitive, stereotyped behavior after higher doses. In these studies MDPV is about equi-potent with MA but is much more efficacious in the self-administration paradigm. Thus these data support a conclusion that MDPV poses a risk for uncontrolled use and dependence that is even greater than that of MA.

Additional Reading:

TLNeuro blog posts on MDPV

Watterson et al. 2012 Potent rewarding and reinforcing effects of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV).

Baumann et al. 2013 Powerful cocaine-like actions of 3,4-Methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive ‘bath salts’ products.

Fantegrossi et al. 2013 In vivo effects of abused ‘bath salt’ constituent 3,4-methylenedioxypyrovalerone (MDPV) in mice: drug discrimination, thermoregulation, and locomotor activity.

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