TL neuro

September 9, 2015

MDPV conditions a place preference in rats; but what about this CTA?

Filed under: Animal Models, Behavior, Cathinones, MDPV — mtaffe @ 10:44 am

A new paper presents what appear to be conflicting results about the rewarding properties of MDPV (“bathsalts”) in rats:

King HE, Wakeford A, Taylor W, Wetzell B, Rice KC, Riley AL. Sex differences in 3,4-methylenedioxypyrovalerone (MDPV)-induced taste avoidance and place preferences. Pharmacol Biochem Behav. 2015 Jul 26;137:16-22 [ PubMed ][ Publisher Link ]

King15-MDPV-CPPKing and colleagues have conducted a conditioning experiment in male and female Sprague-Dawley rats. In outline, place conditioning involves a two-compartment apparatus in which the two sides can be distinguished by tactile, visual and/or odor cues. Typically, a baseline session will be conducted in which the rat is allowed to roam around the entire apparatus (in this experiment for 15 min). The baseline amount of time spent on each side is then recorded. During the conditioning training, animals are injected with a drug (in this study 0.0, 1.8 or 3.2 mg/kg of MDPV, intraperitoneally) and confined in their non-preferred side of the apparatus for 30 min. On alternate days, all animals are injected with saline and confined to their initially-preferred side of the apparatus for 30 min. The key 15 min test, depicted in this graph, comes after 4 repetitions of each training session; the data are represented by the proportion of time spent on the drug-paired side. As you can see, the group of animals that received only saline injections on all eight days changed from the slightly less-preferring baseline test (~39% on the drug-paired side) to no-preference (~50% time spent on each side). In contrast, the groups that got active MDPV doses during active drug conditioning sessions increased the time spent on the drug-paired side (* depicts a significant difference from the 0 dose group on the post-conditioning test). These data are collapsed across the rat sex and the paper indicates that no sex differences were confirmed in the statistical analysis.

This is interpreted as a rewarding effect of MDPV at these doses.

So far so good.

There is a slightly less-intuitive finding in this paper as well.

King15-MDPV-CTAThe authors also conducted a taste-aversion study in the same animals. In a classic Conditioned Tasted Aversion study, rats are allowed to consume some food or fluid that they find palatable, such as saccharin-sweetened water. If the rats are given some treatment that makes them feel bad (such as an injection of lithium chloride) after consuming the highly-palatable food/fluid, they tend to avoid it on a subsequent re-test. In this King study, the investigators allowed the rats to consume saccharin solutions for 20 min just prior to receiving their MDPV injections for the above-described place preference assay. Pretty efficient design!

What you can see from this graph is that the male and female rats that only received saline injections after drinking saccharin (M0 and F0 groups) gradually consumed more saccharin prior to each of the three remaining active-drug conditioning sessions. In contrast, the groups that received MDPV consumed less saccharin solution. The stats symbols are a little complicated on this one so from the paper: [Panel A (males): *M0 significantly greater than M1.8 and M3.2; ^M0 significantly greater than all drug-treated groups; %M1.0 and M1.8 significantly greater than M3.2; #M3.2 significant decrease from Trial 1; αM3.2 significant decrease from Trial 2. Panel B (females); *F0 significantly greater than F1.8 and F3.2; ^F0 and F1.0 significantly greater than F3.2; #F1.0 significant increase from Trial 1.].

Wait, huh? This implies that the animals are expressing feeling bad because of MDPV (hence the Taste Aversion) and feeling good because of MDPV (the Place Preference).

At the same time and from the exact same doses, thanks to this efficient experimental design.

The answer to this conundrum lies in an older paper by Linda Parker.

Parker LA. Rewarding drugs produce taste avoidance, but not taste aversion. Neurosci Biobehav Rev. 1995 Spring;19(1):143-57. [ PubMed ]

Parker95-CTA-AversiveTasteReactionThis paper contrasted changes in sucrose preference induced by lithium chloride versus a number of abused drugs that are are reinforcing in self-administration and place preference assays such as amphetamine, cocaine, nicotine, morphine, etc. There were low/medium dose and high doses tested, I’m including only the high-dose graph here for simplicity but the takeaway message isn’t changed. As you can tell from this high-dose graph, all test drugs except morphine produced a significant reduction in sucrose drinking compared with the injection of saline (CTA). The key part of this study was that the rats were video taped for behavioral scoring by a reviewer blinded to drug treatment condition. Importantly, the rats were scored for Aversive Taste Reactions (ARs) to the drinking spouts / fluid taste. This included gaping, chin rubbing, paw pushing and letting fluid drip from the spout without consuming it. Lithium Chloride and nicotine were the only drugs that resulted in drug-injected rats expressing more ARs to the sucrose on the test day compared with the saline-injected rats. This implies, as the author underlined in discussion comments, that the mechanisms by which saccharin preference is reduced differs. Sometimes when a CTA is produced in a rat, it really is a reflection of the conditioning process making the rat find the saccharin taste unpleasant. Other times, the conditioning process doesn’t make the taste unpleasant, but rats certainly find it less pleasurable, reinforcing or rewarding.

In slightly different language, we might interpret this as meaning that the experience of the type of pleasurable experience caused by drugs of abuse can diminish the value of other stimuli or experiences that rats would otherwise find to be pleasurable.

This interpretation dovetails nicely with our prior paper in which rats were permitted to both self-administer MDPV intravenously and to run on an activity wheel [see blog post]. What we found was that as the rats initiate the consistent self-administration of MDPV, they decrease the amount of wheel activity that they engage in. That study was consistent with an earlier one we published showing that self-administration of methamphetamine also gradually decreases the amount rats will use the activity wheel [ see blog post ].

We interpret this phenomenon to reflect the drug stimulus devaluing the degree to to which a rat finds wheel activity rewarding.

As such, this gives us an animal model to further explore concepts that may explain why some individuals who use drugs regularly become addicted whereas some other individuals can cease drug use. The comparative value of other sources of reinforcement (social, family, vocational, recreational, etc) versus the drug experience may be a critical determinant of who will spiral into a compulsive drug use problem.

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Additional reading: Hunt and Amit, 1987.

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