CPDD Annual Meeting 2011!!!!!111111!!!!!

Did I mention I enjoy learning more about the neurobiological and behavioral effects of recreational drugs as well as the development and treatment of addictions?

The College on Problems of Drug Dependence will be holding their annual meeting in Hollywood Florida this upcoming week. I’ve been going through the Itinerary Planner and Program Book to get a preview. There are a few presentations that touch on topics that we’ve blogged about here at the DrugMonkey blog, including

-treating the hyponatremia associated with MDMA-induced medical emergency

–vaccination against drug abuse

–exercise as a potential therapy for, or antidote against, stimulant drug addiction

-JWH-018 and other synthetic cannabinoid constituents of Spice/K2 and similar “incense” products

-some preclinical studies on mephedrone / 4-methylmethcathinone

-presentations from the DEA on scheduling actions that are in progress

I’m certainly looking forward to seeing a lot of interesting new data over the next week.

An Opiate Antagonist Precipitates Withdrawal…From Exercise.

In my prior post, I overviewed a pair of papers which suggested the possibility that rats provided with running wheels might be used to model exercise addiction. The application hinged on a finding that when rats are provided with longer term 4 or 24 hr access to a wheel they gradually escalate their running over the course of about three weeks; this effect is greater than any increases seen when rats have wheel access for only an hour or two. As I alluded to, however, confidence in wheel running as a model of human exercise addiction akin to substance dependence is going to require a lot more converging evidence.

Kanarek and colleagues have provided some of this converging evidence. The authors examined the effects of challenge with the opiate antagonist naloxone in groups of male and female rats which had been permitted to run on an activity wheel.

This study relies on an effect* which has been known for quite some time, namely that the acute administration of low doses of drugs which block mu opiate receptors can rapidly precipitate withdrawal signs in rats or mice which have been treated chronically with morphine, heroin or other mu opiate agonists. Withdrawal signs that are similar in appearance to those that emerge with spontaneous withdrawal of the animal from chronic exposure to opiates. As Marshall and Weinstock observed in 1969, withdrawal symptoms could be quantified as an index of opiate dependence.

The purpose was to determine whether the number of jumps elicited by nalorphine in groups of mice could be used as a method of measuring the intensity of the withdrawal syndrome…The number of jumps was a monotonic increasing function of both the number of injections and the total dose [of morphine-DM] injected…In conclusion it is suggested that the number of jumps elicited by an antagonist in chronically narcotized mice can be used as a quantitative measure of the withdrawal syndrome.

Kanarek and colleagues were thus not just hypothesizing that they could precipitate withdrawal differentially in exercised animals, but also that the neuropharmacological change associated with exercise involved endogenous opioids. To wit, the endorphins which have been speculated in common use to underlie the so-called runner’s high.

The study is a bit complicated because it includes a manipulation termed Activity-Based Anorexia. Apparently if you give rats access to food for only an hour a day, they can survive with approximately normal maintenance of weight but if you also provide them with an activity wheel, they stop eating and drop weight-even to the point of death. This is a mere distraction for the present purpose, however, since the effect of challenge with the opiate antagonist was not qualitatively changed by the feeding condition. Nevertheless, the designs were between groups with factors of wheel access and feeding condition (24 hr food vs 1 hr food). There was also an additional yoked-pair feeding group which was inactive but fed the same amount of food consumed by the 1-hr / wheel access animals. This is by way of explaining the graphs, but the key effect for today’s discussion lies in the main effect of exercise condition.

The first experiment was conducted in female rats permitted wheel access for 7 days (plus sedentary groups) and then initiated on the 1 hr / 24 hr / yoked feeding conditions. The naloxone challenge (1 mg/kg) was initiated after 3-6 days when the 1 hr / activity group had dropped to 80% of their initial bodyweight. Since individuals took different numbers of days to reach this criterion, matched numbers of animals from the other groups were challenged with naloxone on the days over which the critical group reached criterion. Traditional withdrawal symptoms were scored.

As you can see in the Figure, withdrawal was precipitated more robustly in the group which had been permitted to exercise on the wheel and received 1 hr access to food, relative to the remaining groups. The authors also reported a correlation between total withdrawal signs exhibited by an individual and the wheel activity on the day before naloxone challenge in all activity rats but this was attributable to the food restricted subgroup. Similar results were found when they assessed the number of rats expressing a given withdrawal symptom, instead of the overall withdrawal score, as shown in the Table.

The second experiment was conducted in males with similar wheel access and feeding groups. In this case, however, the males in the exercise groups were permitted 25 days of wheel access (instead of the 7 used for the females) prior to initiation of the feeding conditions. Again, naloxone challenges were conducted when the 1-hr feeding / Wheel access group dropped to 80% of their prior weight.

Effects of naloxone challenge were most pronounced in exercised rats however in this case the effect did not depend on feeding condition. The graph of the mean total withdrawal scores shows that naloxone precipitated more signs of withdrawal in the 24-hr feeding / Wheel access group than in the sedentary groups.

So why the difference in the 24-hr feeding / wheel access condition between the experiments? I think the most likely issue is the difference in wheel access duration prior to the food conditions. The males, although they ran less than the females, escalated their running through about 16 days of access and had plateaued by the start of the food-access manipulation at day 25. The females were still increasing their running at the end of 7 days and into the food manipulation condition, but very likely had not completely expressed the commonly observed increase in daily running associated with 24 hr access over ~3-4 weeks duration.

In some senses these two experiments are not discordant but rather complement each other. Together they point out that the amount of activity on a wheel is not sufficient to increase liability for precipitated withdrawal. The females in the 24-hr feeding condition peaked at about 21,000 revolutions per day whereas the males in the 1-hr feeding condition peaked at about 8,500 revolutions per day. Only the latter exhibited increased withdrawal signs after naloxone when compared with their inactive control group. This suggests that it is the relative increase from baseline activity levels that is most important, rather than the spontaneous difference in baseline running.

And that interpretation, DearReader, is consistent with the idea that repeatedly engaging in physical activity can disrupt the neuronal mechanisms that subserve the rewarding aspects of that exercise. This disruption can then be observed as withdrawal signs, given acute administration of an opiate antagonist. This further suggests that endogenous opioids may be critically involved in the rewarding, and therefore addictive, aspects of repetitive exercise.

As with the behavioral escalation papers I previously discussed, this is not in and of itself proof that rats are addicted to, or become dependent on, wheel running.
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A PubMed search for naloxone precipitated withdrawal finds 1135 references.

Kanarek RB, D’Anci KE, Jurdak N, & Mathes WF (2009). Running and addiction: precipitated withdrawal in a rat model of activity-based anorexia. Behavioral neuroscience, 123 (4), 905-12 PMID: 19634951

Marshall I, & Weinstock M (1969). A quantitative method for the assessment of physical dependence on narcotic analgesics in mice. British journal of pharmacology, 37 (2) PMID: 5388579

Is Exercise Addictive?

Athletes, particularly those that engage in the sustained-activity aerobic sports such as running, cycling and Nordic skiiing, are occasionally to be found describing their chosen physical activity as addictive. Some of them talk about symptoms of anxiety and depression and discomfort when not permitted to engage in their usual level of activity due to injury or other life circumstances. These can sound suspiciously like syndromes associated with addictive drugs, to those of us who are familiar with the type and aware that drug “withdrawal” is not limited to the dramatic symptoms associated with withdrawal from a substantial intravenous heroin addiction.

Is this real, though? Is there something neurobiologically similar to drug addiction about what can happen to the brain in the course of a sustained aerobic exercise habit? To answer these questions it helps, of course, to have an animal model, preferably one that has a lot of similarity to our drug-abuse models.

Eikelboom and Lattanzio published two papers in 2003 that proposed a possible model of exercise-dependence using activity wheels in rats. You will be familiar with the notion that hamsters, rats and mice  will run on a treadwheel under single-housed conditions from your local pet store. Drop by one on your way home today if you don’t know what I mean. There is also an older behavioral literature that shows that wheel access can act as a reinforcer in laboratory rats- they will press a lever to get a brief interval of wheel running. Manipulating the length of time they can run on the wheel acts, to a first approximation, like manipulating the number of food pellets delivered in a traditional setup.

But just because something is chosen voluntarily and acts as a reinforcer does not necessarily mean that it can model compulsive, repetitive behavioral patterns. It does not necessarily mean that it will tap into the disruption of brain reward pathways and mechanisms that is the hallmark of substance dependency. For this we need a little more evidence, starting with behavior and moving into neurobiology as the evidence mounts.

The background for the Lattanzio and Eikelboom work is  the Ahmed and Koob 1998 paper which has become hugely influential in substance abuse models. The short version was that instead of permitting rats an hour of access to intravenous cocaine each day, they permitted the animals 6 hours of access per day. They observed that the 6-hr (termed “Long Access”) group took more cocaine than animals run in the traditional 1-hour sessions, perhaps unsurprisingly given the increased opportunity. More importantly, as the sessions of longer access continued, the rats took an ever increasing amount including in the first hour of access. Not only that, but the Long Access group took more cocaine in the very first 10 minutes of the session.  This seminal paper has been followed by a lot of additional evidence that this change in the Long Access group is brought about by lasting disruptions of common reward mechanisms.

[Sidebar: You will recall from my posts trying to work out the conditional probability of dependence, that I am not a fan of simple, drug-feels-good models of drug reinforcement; even though they have a place. The short version of my thinking is that we already know from the human epidemiology that a large fraction of the individuals who find that drugs make them feel good do not go on to develop dependence, addiction or what we might term a drug problem. Animal models that move on from the simple feels-good stage of drug taking resonate more strongly with me.]

Lattanzio and Eikelboom set out to provide rats with longer and shorter access to wheel running and see if there was behavioral evidence of the sort of “escalation” that was reported by Ahmed and Koob.

In the first paper the authors compared wheel running in rats who had 24/7 access to the wheel to rats who had only a two hours of access for 24 days. As depicted in the first figure, wheel activity gradually increased in the 24/7 group across the three weeks of study. This is pretty consistent with my reading of the circadian literature and has some interesting implications with respect to the development of aerobic fitness. Activity in the 2-hour group remained stable.

So far so good. They also show that the 24/7 animals ran more in a comparable 2-hr interval, reminiscent of the key first-hour comparison in the drug self-administration paradigm.

Or, they sort of show that.

When they selected the same two-hour interval of the day in which the 2-hr group was exposed to the wheel, the 24-hr animals ran less. A lot less. Because. they. ran. the. 2-hr. group. in. the. light. cycle. Rats are nocturnal and more active in the dark. So when the authors (cherry) picked the most-active 2-hr interval in the 24/7 access group, then yes, it looked like an escalation across the days of training.

Frustrating. A hint of an escalation type of effect with longer access to the wheel but confounded by an inexplicable choice to run the short-access group in the light part of the cycle. Luckily, the authors did not leave off at this one study.

The second paper is more interesting because they run both the longer and shorter sessions in the dark, when rats are most active. In addition they are pitting 1 hr access against only 4 hours of wheel access, instead of a full 24 hrs. So it makes it a little more comparable to the typical drug self-administration experiment. These results are again consistent with escalation of wheel running. In Figure 2B they show that the 4-hour group’s wheel running in the first two hours of access increased substantially more with sequential training sessions in comparison with the 1-hour group’s running.

These papers are, to my eye, a good first attempt at a model. This is not the answer to whether exercise is addictive or becomes a compulsive behavior similar to drug self-administration. However it shows that we can now go on to ask additional questions which might answer the question. Are the brains of the longer-access rats changing in the same way that the long-access to cocaine rats’ brains change? Are they in a state of reward deficit (disrupted allostasis in the Ahmed/Koob handwaving) that generalizes across reinforcers?

If evidence develops for this, we can only then move on to the larger issues. Does a substantial history of exercise leave individuals at risk for reward-related disorders when they stop exercising? Are they at increased liability for compulsive eating or drug abuse? If so, what is the threshold? Etc. Really, there is a lot of fascinating research ahead on this topic.

I have a few current questions about the exercise physiology angle because I know there is a blogger or two around and about that might have some information. Are the physiological changes brought about by wheel running in laboratory rats similar to those we might expect from a human in aerobic conditioning training? The circadian literature shows pretty consistently, to my eye, that daily running in rats given 24/7 access to wheels increases over a several week interval to reach a sustained plateau of daily activity. This suggests that there are perhaps cardiovascular and muscular adaptations at play, in a word “fitness”. But then again the sort of exercise that results in human conditioning is sort of aversive at the start, isn’t it? We force ourselves to do it because we want to be fit or to race or whatever. We don’t do it because every step of the 6 mi run is pure bliss right off the couch, right? So why would rats voluntarily run themselves into this sort of conditioning effect?

Those of us who are looking at this from a perspective of reward mechanisms will eventually need to show that wheel “escalation” is not just a result of a conditioning effect which permits the rats to run for longer distances. Or for that matter a motor skill effect which permits them to tread the wheel bars more efficiently.

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Disclaimer: See the Disclaimer page for the usual about my conflicts when it comes to drug abuse research topics. Also, I am professionally acquainted with some of the authors of the work under discussion in this post.

Literature Cited:
Ahmed SH, & Koob GF (1998). Transition from moderate to excessive drug intake: change in hedonic set point. Science (New York, N.Y.), 282 (5387), 298-300 PMID: 9765157
Lattanzio SB, & Eikelboom R (2003). Wheel access duration in rats: I. Effects on feeding and running. Behavioral neuroscience, 117 (3), 496-504 PMID: 12802878
Eikelboom R, & Lattanzio SB (2003). Wheel access duration in rats: II. Day-night and within-session changes. Behavioral neuroscience, 117 (4), 825-32 PMID: 12931966