TL neuro

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.

   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.

activity wheel picture from Med Associates, Inc

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.

August 15, 2011

Concurrent Methamphetamine IVSA and Wheel Activity Paper

Filed under: Exercise, Methamphetamine — mtaffe @ 9:45 am

The following has been accepted for publication:

Miller, M.L., Vaillancourt, B.D., Wright Jr., M.J., Aarde, S.M., Vandewater, S.A., Creehan, K.M. and Taffe, M.A. Reciprocal inhibitory effects of intravenous d-methamphetamine self-administration and wheel activity in rats, 2012, Drug Alcohol Depend, 121:90-96 [Sep 5, 2011 Epub ahead of print]

In this paper we show that when rats are provided concurrent access to an activity wheel during the initial acquisition of methamphetamine self-administration, they take less drug.

In addition, a prior history of 7 or 14 self-administration sessions reduces the amount rats will subsequently run on the wheel when provided with concurrent access.

Additional reading:
Smith et al 2011b, 2011a, 2008b, 2008a

Lynch et al, 2010

Cosgrove et al 2002

November 19, 2010

Cosgrove et al, 2002: Wheel running suppresses cocaine taking

Filed under: Cocaine, Exercise — mtaffe @ 10:44 am

In 2008 at the Annual Meeting of CPDD, I heard Nora Volkow, Director of NIDA, describe a new interest of NIDA in the role that regular exercise plays in preventing or ameliorating drug use. Some of the rationale was epidemiological, you may think of this as “adolescents who are in sports are less likely to do drugs”. It was backed by a little bit of evidence that adding exercise to a smoking cessation program may have some additional benefit.

K. P. Cosgrove, R. G. Hunter and M. E. Carroll. Wheel-running attenuates intravenous cocaine self-administration in rats: Sex differences. Pharmacology, Biochemistry and Behavior 73 (2002) 663–671

ResearchBlogging.orgThe study used male and female Sprague-Dawley rats which were individually housed in a 12 hr light/dark cycle. Experimental sessions (wheel or drug access) were 6 hours in length and conducted in the light portion of the cycle (i.e., inactive for this nocturnal species). Rats were first were habituated to 24 hr / day access to activity wheels for at least 14 days or until running patterns stabilized. Thereafter they were implanted with intravenous catheters for self-administration testing. The key experimental conditions first provided five days in which animals were permitted to press a lever to receive cocaine infusions. In the next 5 sessions, animals were allowed access to cocaine as well as the activity wheel. The third block of 5 sessions permitted access only to cocaine. In the final block, animals were permitted access to the running wheel only (although only 3 subjects participated in this stage of the experiment). (more…)

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