Enhancement of amphetamine-induced locomotor response in rats on different regimens of diet restriction and 2-deoxy-d-glucose treatment

Diet restriction (DR) in rodents increases lifespan, reduces age-related disease and pathology, increases stress responses, and maintains better function later into life compared with conventional ad libitum (AL) feeding. We have been investigating different DR regimens and also DR mimetics that stimulate stress response pathways that are activated by DR. By inhibiting glycolysis, feeding or injection of 2-deoxy-d-glucose (2DG) has been proposed as a DR mimetic and has been shown to provide neuroprotection. In the current study, we examined whether 2DG treatment produces behavioral changes similar to those observed in DR rats following stimulation of the dopaminergic (DA) system by d-amphetamine (AMPH). Male Fischer 344 rats were maintained on different dietary regimens: 40% daily DR (40% DR); every-other-day feeding (EOD); or AL with some groups provided food containing 0.4% 2DG or injected i.p. with 2DG. In addition, we examined the persistence of effects of DR or 2DG feeding after switching rats to AL. When locomotor activity was assessed at different time points following initiation of dietary treatments, we noted that the enhancement of AMPH-induced locomotor responses emerged earlier in DR rats than observed in 2DG fed rats, but 40% DR and EOD rats responded in a similar manner. Enhanced locomotor responses persisted in 2DG fed rats even when returned to normal diet for 1 month and in the case of DR rats even after 2 months of AL feeding. Three weeks of 2DG injections also enhanced AMPH response, but this effect was transient. The most important finding was that 2DG did not affect body weight or diet intake yet had effects similar to DR. Thus, 2DG appears to activate DA pathways in the same direction as DR does but without the necessity of reducing caloric intake.