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 -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 -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 -opioid receptor antagonist ␤-funaltrexamine (␤-FNA) into area CA3. We found that -opioid receptor binding decreased 24 hr after ␤-FNA injection and returned to control levels 11 d after injection. Injections of ␤-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 -opioid receptor levels replenished (Ͼ11 d after injection). In pretrained animals, ␤-FNA significantly impaired spatial memory retrieval and new (reversal) learning. These data are consistent with theoretical models of CA3 function and suggest that CA3 -opioid receptors play an important role in the acquisition and retrieval of spatial memory.

Distinct Patterns of Neural Activation Associated with Ethanol Seeking: Effects of Naltrexone

“…The HIPPO contains a high density of opioid receptors (Mansour et al 1987) and opioids modulate learning and memory-related events in this brain region (Bramham and Sarvey 1996;Jamot et al 2003;Jang et al 2003;Simmons and Chavkin 1996). Moreover, μ-opioid receptor antagonist injections into the dorsal HIPPO impair spatial memory retrieval (Meilandt et al 2004). Thus, the suppression of S + -elicited neural activation in the HIPPO may reflect NTX-mediated dampening of learned contextual associations between environmental stimuli and drug reward, leading to reduced drug-seeking normally evoked by such cues.…”

Topography of Arc/Arg3.1 mRNA Expression in the Dorsal and Ventral Hippocampus Induced by Recent and Remote Spatial Memory Recall: Dissociation of CA3 and CA1 Activation

“…Numerous early and recent studies demonstrated that a flat retrograde amnesia was induced by lesions of dHC and the entire HC at 0.5-3.5 months in watermaze memory retention (Bolhuis et al, 1994;Mumby et al, 1999; logical changes found in CA3 stratum oriens (Ramirez-Amaya et al, 2001) and may indicate involvement of the CA3 autoassociative network in recent (Nakazawa et al, 2002(Nakazawa et al, , 2003Meilandt et al, 2004) as well as in long-term memory storage and recall. Mapping data support the idea that DG is not only involved in memory encoding but also participates in memory retrieval (Nanry et al, 1989;Lisman, 1999).…”

The Role of Amygdalar Mu-Opioid Receptors in Anxiety-Related Responses in Two Rat Models

“…Cyclodextrin is a cyclic sucrose array that increases drug solubility but is inert and secreted rapidly (see Wall and Messier, 2000), and injection of this vehicle had no effect (compared with other control groups) on anxiety or activity measures. Meilandt et al (2004) demonstrated that injections of FNA could depress MOR binding in the hippocampus after such injections by as much as 49% at 24 h, and decreases persisted for up to 11 days (Meilandt et al, 2004). This dose of FNA in the nucleus accumbens can also block the effects of DAMGO-induced feeding at 24 h (Ragnauth et al, 2000).…”