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 methamphetamineĀ  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.

Implications:
   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.

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activity wheel picture from Med Associates, Inc

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