Mu-opioid receptor inhibition decreases voluntary wheel running in a dopamine-dependent manner in rats bred for high voluntary running

Booth et. al.

Neuroscience

                Physical inactivity has been associated with many disease states including hypertension, cognitive dysfunction and other diseases. Rodent studies have shown that there is a genetic component in amount of voluntary physical activity and this laboratory has selectively bred rat models to study the difference between high and low physical activity. This paper tested the hypothesis that the dopamine and opioid systems interact to influence physical activity, specifically the motivation to run. The dopamine system in the midbrain is important for the motivation to run and this system is partly regulated by endogenous opioids. For all experiments High Voluntary Running (HVR) bred rats and Low Voluntary Running (LVR) rats were used. All rats were female.

                In experiment one inherent differences in opioid receptor expression and function were assessed in sedentary HVR and LVR rats. Rats were sacrificed at 8 weeks of age and opioid receptor mRNA levels were assessed in multiple areas of the midbrain. It was found the in HVR rats there was a significantly higher expression of opioid receptor mRNA and protein in the nucleus accumbens and a significantly higher expression of just the mRNA in the acruate nucleus.

                In experiment 2 the effects of the opioid antagonist naltrexone were assessed for neuronal activation in multiple areas of the midbrain. Fos was used as a measure of neuronal activation. This experiment showed that injection of naltrexone intraperitoneally significantly reduced Fos expression in the nucleus accumbens, acruate nucleus in the HVR rats but not the LVR rats.

In experiment 3 both HVR and LVR rats were given intraperitoneal injections of naltrexone and then wheel running and food intake were measured. All rats were given injection on the night of proestrus. This experiment showed that HVR rats were running more than LVR rats as expected, however, injection of naltrexone significantly decreased wheel running of HVR rats but not LVR rats. Food intake was also decreased in HVR rats but not LVR rats.

In experiment 4 nucleus accumbens dopamine nerve terminals were ablated and then running distance and food intake were measured. This experiment found that ablation of the dopamine nerve terminals did not have a significant effect on its own on running activity, however, when paired with injections of naltrexone, naltrexone no longer had the effect of decreasing running activity.

The major findings of this paper are that opioid receptor expression is higher in nucleus accumbens of sedentary HVR rats compared to LVR rats, opioid antagonism decreases mRNA’s associated with dopamine signaling in HVR but not LVR rats, naltrexone reduces wheel running in HVR but not LVR rats, and HVR rats with ablated dopaminergic terminals in nucleus accumbens are refractory to the decreases in wheel running associated with naltrexone. This paper postulates novel ideas for the interactions between the opioid and dopamine systems in the genesis of voluntary wheel running.

Ben R