Parameters for abolishing conditioned place preference for cocaine from running and environmental enrichment in male C57BL/6J mice.

RATIONALE: Evidence suggests that 4 weeks of voluntary wheel running abolishes conditioned place preference (CPP) for cocaine in male C57BL/6J mice. OBJECTIVES: To determine the duration and timing of exposure to running wheels necessary to reduce CPP, and the extent to which the running per se influences CPP as compared to environmental enrichment without running. METHODS: A total of 239 males were conditioned for 4days twice daily with cocaine (10mg/kg) and then split into 7 intervention groups prior to 4days of CPP testing. Experiment 1 consisted of two groups housed as follows: short sedentary group (SS; n=20) in normal cages for 1 week; the short running group (SR; n=20) with running wheels for 1 week. Experiment 2 consisted of five groups housed as follows; short 1 week of running followed by a 3 week sedentary period (SRS; n=20); a 3 week sedentary period followed by 1 week of running (SSR; n=20); long sedentary group (LS; n=66) in normal cages for 4 weeks; long running group (LR; n=66) with running wheels for 4 weeks; and long environmental enrichment group (EE; n=27) with toys for 4 weeks. RESULTS: Levels of running were similar in all running groups. Both running and environmental enrichment reduced CPP relative to sedentary groups. CONCLUSIONS: Results suggest that the abolishment of cocaine CPP from running is robust and occurs with as low as 1 week of intervention but may be related to enrichment component of running rather than physical activity.

Increased adult hippocampal neurogenesis is not necessary for wheel running to abolish conditioned place preference for cocaine in mice.

Recent evidence suggests that wheel running can abolish conditioned place preference (CPP) for cocaine in mice. Running significantly increases the number of new neurons in the hippocampus, and new neurons have been hypothesised to enhance plasticity and behavioral flexibility. Therefore, we tested the hypothesis that increased neurogenesis was necessary for exercise to abolish cocaine CPP. Male nestin-thymidine kinase transgenic mice were conditioned with cocaine, and then housed with or without running wheels for 32 days. Half of the mice were fed chow containing valganciclovir to induce apoptosis in newly divided neurons, and the other half were fed standard chow. For the first 10 days, mice received daily injections of bromodeoxyuridine (BrdU) to label dividing cells. On the last 4 days, mice were tested for CPP, and then euthanized for measurement of adult hippocampal neurogenesis by counting the number of BrdU-positive neurons in the dentate gyrus. Levels of running were similar in mice fed valganciclovir-containing chow and normal chow. Valganciclovir significantly reduced the numbers of neurons (BrdU-positive/NeuN-positive) in the dentate gyrus of both sedentary mice and runner mice. Valganciclovir-fed runner mice showed similar levels of neurogenesis as sedentary, normal-fed controls. However, valganciclovir-fed runner mice showed the same abolishment of CPP as runner mice with intact neurogenesis. The results demonstrate that elevated adult hippocampal neurogenesis resulting from running is not necessary for running to abolish cocaine CPP in mice.

Aerobic exercise is the critical variable in an enriched environment that increases hippocampal neurogenesis and water maze learning in male C57BL/6J mice.

Previous studies have shown that housing mice with toys and running wheels increases adult hippocampal neurogenesis and enhances performance on the water maze. However, the relative contribution of running versus enrichment to the neurogenic and pro-cognitive effects is not clear. Recently, it was demonstrated that enrichment devoid of running wheels does not significantly enhance adult hippocampal neurogenesis in female C57BL/6J mice. However, novel toys were not rotated into the cages, and dietary enrichment was not included, so it could be argued that the environment was not enriched enough. In addition, only females were studied, and animals were group-housed, making it impossible to record individual running behavior or to determine the time spent running versus exploring the toys. Therefore, we repeated the study in singly housed male C57BL/6J mice and enhanced enrichment by rotating novel tactile, visual, dietary, auditory, and vestibular stimuli into the cages. Mice were housed for 32 days in one of four groups: running-only, enrichment-only, running plus enrichment, and standard cage. The first 10 days bromodeoxyuridine (BrdU) was administered to label dividing cells. The last 5 days mice were tested on the water maze, and then euthanized to measure number of BrdU cells co-labeled with neuronal nuclear marker (NeuN) in the dentate gyrus. Mice in the running-only group ran, on average, equivalent distances as animals in the running plus enrichment group. The combination of enrichment and running did not significantly increase hippocampal neurogenesis any more than running alone did. Animals in the running-only condition were the only group to show enhanced acquisition on water maze relative to standard cage controls. We confirm and extend the conclusion that environmental enrichment alone does not significantly increase hippocampal neurogenesis or bestow spatial learning benefits in male C57BL/6J mice, even when the modalities of enrichment are very broad.