Drug Conditioning and Sensitization in Mice: Importance of Early Voluntary Exercise

The timing of voluntary exercise relative to drug conditioning is important to its "neuroprotective" effects, though it is unclear whether the voluntary exercise needs to occur temporally contiguous with drug conditioning, or occur during an early, developmental period, but non-contiguous with drug conditioning, for its "neuroprotective" effects. To distinguish between these two ideas, the timing of voluntary exercise relative to drug conditioning on the development and extinction of conditioned hyperactivity, and induction of sensitization was manipulated in the present experiment. Specifically, half of the exercise mice were permitted access to home-cage running wheels for 6 continuous weeks (Exercise-Exercise) whereas the other half of the exercise mice were permitted access to home-cage running wheels only for the first 3  weeks and then had the wheels removed (Exercise-Sedentary). Likewise, half of the sedentary mice had no home-cage running wheels for 6 continuous weeks (Sedentary-Sedentary) whereas the other half of the sedentary mice were permitted access to the home-cage running wheels for the last 3 weeks prior to the acquisition phase (Sedentary-Exercise). Mice received vehicle or methamphetamine (Meth; 1.0 mg/kg; acquisition), followed by saline-alone sessions (extinction) and finally challenged with an escalating Meth-regimen (0.25 → 1.0 mg/kg). While all Meth-paired groups, regardless of exercise regimen, showed conditioned hyperactivity, Exercise-Exercise and Exercise-Sedentary mice were less responsive to chronic Meth exposure and showed slower extinction compared to the other Meth-paired groups. These results suggest an early exercise regimen, during a critical developmental window, protects against the stimulant properties of Meth and simultaneously facilitates contextual learning.