TL neuro

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.


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