Role of Hippocampal CA3 μ-Opioid Receptors in Spatial Learning and Memory

Abstract

The dorsal CA3 region of the hippocampus is unique in its connectivity, sensitivity to neurotoxic lesions, and its ability to encode and retrieve episodic memories. Computational models of the CA3 region predict that blocking mossy-fiber and/or perforant path activity to CA3 would cause impairments in learning and recall of spatial memory, respectively. Because the CA3 region contains μ-opioid receptors and receives inputs from the mossy-fiber and lateral perforant pathways, both of which contain and release opioid peptides, we tested the hypothesis that inactivating μ-opioid receptors in the CA3 region would cause spatial learning and memory impairments and retrieval deficits. In this study, male Sprague Dawley rats were trained in a Morris water maze after a single bilateral intrahippocampal injection of either saline or the selective and irreversible μ-opioid receptor antagonist β-funaltrexamine (β-FNA) into area CA3. We found that μ-opioid receptor binding decreased 24 hr after β-FNA injection and returned to control levels 11 d after injection. Injections of β-FNA into the CA3 region, but not into the ventricles, caused a significant impairment in the acquisition of spatial learning without causing sensory or motor deficits. New learning was not affected once μ-opioid receptor levels replenished (>11 d after injection). In pretrained animals, β-FNA significantly impaired spatial memory retrieval and new (reversal) learning. These data are consistent with theoretical models of CA3 function and suggest that CA3 μ-opioid receptors play an important role in the acquisition and retrieval of spatial memory.