Differential regulation of hippocampal progenitor proliferation by opioid receptor antagonists in running and non‐running spontaneously hypertensive rats

Abstract

Voluntary running in mice and forced treadmill running in rats have been shown to increase the amount of proliferating cells in the hippocampus. Little is known as yet about the mechanisms involved in these processes. It is well known that the endogenous opioid system is affected during running and other forms of physical exercise. In this study, we evaluated the involvement of the endogenous opioids in the regulation of hippocampal proliferation in non-running and voluntary running rats. Nine days of wheel running was compared with non-running in spontaneously hypertensive rats (SHR), a rat strain known to run voluntarily. On the last 2 days of the experimental period all rats received two daily injections of the opioid receptor antagonists naltrexone or naltrindole together with injections of bromodeoxyuridine to label dividing cells. Brain sections from the running rats showed approximately a five-fold increase in newly generated cells in the hippocampus, and this increase was partly reduced by naltrexone but not by naltrindole. By contrast, both naltrexone and naltrindole increased hippocampal proliferation in non-running rats. In non-running rats the administration of naltrexone decreased corticosterone levels and adrenal gland weights, whereas no significant effects on these parameters could be detected for naltrindole. However, adrenal gland weights were increased in naltrexone- but not in naltrindole-administered running rats. In addition, in voluntary running rats there was a three-fold increase in the hippocampal levels of Met-enkephalin-Arg-Phe compared with non-runners, indicating an increase in opioid activity in the hippocampus during running. These data suggest an involvement of endogenous opioids in the regulation of hippocampal proliferation in non-running rats, probably through hypothalamic-pituitary-adrenal axis modulation. During voluntary running in SHR naltrexone altered hippocampal proliferation via as yet unknown mechanisms.

Extended Voluntary Running Inhibits Exercise-Induced Adult Hippocampal Progenitor Proliferation in the Spontaneously Hypertensive Rat

“…We have previously shown that stress-related parameters are not changed after 9 days of voluntary running, and in these experiments, a positive effect on hippocampal progenitor proliferation is seen from running (Persson et al 2004). However, long-term exercise has been related to stress perturbations, and this has led us to question if longer periods of running might at some stage become stressful and negatively impact on hippocampal progenitor proliferation.…”

“…The hippocampus is a part of the brain primarily involved in memory and learning (Gould et al 1999;Shapiro 2001), and the hippocampus has been identified as being vulnerable to stress and increased glucocorticoid levels (Cameron and Gould 1994;Kim and Diamond 2002). Voluntary exercise has been shown to increase the number of dividing cells in the granule cell layer (GCL) of the dentate gyrus in mice (Holmes et al 2004;van Praag et al 1999b), in treadmill-exercised rats (Carro et al 2001), and in voluntary running rats (Persson et al 2004). Voluntary exercise has also been shown to increase long-term potentiation and spatial memory in mice (van Praag et al 1999a).…”

Knockout of the mu opioid receptor enhances the survival of adult-generated hippocampal granule cell neurons

“…This multiple opioid receptor antagonism could mask MOR-specific effects. Contradictory results have also been found with naltrexone's effects on cell proliferation in the SGZ (Persson et al, 2004, Galea et al, 2006, emphasizing the complexity of in vivo use of this compound, and the general challenges associated with attempts to mimic genetic manipulation with pharmacological blockade. Future studies will circumvent the natural confounds associated with constitutive KOs and the non-specificity of available MOR antagonists by studying the link between MOR and cell survival in a conditional MOR KO mouse.…”

Long-lasting suppression of hippocampal cell proliferation and impaired cognitive performance by methotrexate in the rat

“…The formation of new neurons out of stem cells in the dentate gyrus of hippocampus (neurogenesis) is thought to play an important role in learning and memory processes [11]. Studies have shown that aging [5], or stress [17] has a negative effect on neurogenesis and cognition, whereas an enriched environment [23], or running wheel activity [29] increases neurogenesis and cognitive performance.…”