The role of mu-opioid receptors in spatial learning and memory

The experiments outlined and performed in this dissertation investigate how μ-opioid receptors modulate acquisition, retention, and retrieval of spatial memory by (1) pharmacologically inactivating μ-opioid receptors in the dorsal CA3 region of the hippocampus in rats and (2) by utilizing gene knockout technology to completely remove μ-opioid receptors from mice to determine the effect on spatial and non-spatial learning and mossy-fiber synaptic plasticity.; Results from this dissertation provide evidence that μ-opioid receptors in the dorsal CA3 region of the hippocampus are intimately involved in the acquisition and retrieval of spatial memory in the Morris water maze. Blocking CA3 μ-opioid receptors with the irreversible antagonist β-funaltrexamine (β-FNA) 24 hrs prior to training impaired spatial water maze learning and retention, whereas blocking μ-opioid receptors after learning impaired spatial memory retrieval and new learning. These results provide behavioral evidence in support of several computational models of CA3 function and suggest that the modulation of synaptic plasticity in the mossy-fiber and lateral perforant pathways to CA3 by μ-opioid receptors plays an important role in memory encoding and retrieval.; This hypothesis was tested in μ-opioid receptor deficient mice, yielding interesting findings. Deletion of the μ-opioid receptor gene did not significantly impair acquisition of spatial water maze learning. Compared to wild-type (+/+) mice, heterozygous (+/−) knockout mice were impaired in spatial memory formation and spatial memory retention, whereas the homozygous (−/−) knockout mice displayed enhanced spatial memory retention. Habituation training in an open field revealed increased locomotor activity in the heterozygous (+/−) knockout mice compared with wild-type (+/+) mice. In the novel object recognition task, no significant differences in short-term (30 min) recognition memory were found, however the heterozygous (+/−) and homozygous (−/−) knockout mice exhibited enhanced long-term (24 hr) recognition memory compared with wild-type (+/+) mice. These results support previous findings that μ-opioid receptor blockade in the brain and periphery enhance memory retention for certain tasks, including the water maze. Finally, the finding that no significant differences were found in mossy-fiber paired-pulse facilitation or mossy-fiber LTP between the wild-type (+/+), heterozygous (+/−), and homozygous (−/−) knockout mice may be due to receptor compensatory mechanisms.