The role of norepinephrine in spatial reference and spatial working memory

The adrenergic system (utilizing norepinephrine, NE, as a neurotransmitter) is implicated in hippocampusbased learning and memory, in addition to its well known peripheral actions mediated by the sympathetic nervous system. We have produced a strain of mice in which the gene coding for the enzyme dopamine betahydroxylase (Dbh), which catalyzes the synthesis of NE from dopamine, has been disrupted. Mice recessive (Dbh-/-) for the Dbh gene mutation lack endogenous NE and epinephrine, while heterozygous mice (Dbh+/-) have normal levels of NE and epinephrine and display normal phenotype. Previous studies have indicated that NE is necessary and sufficient for the retrieval of intermediate-term contextual and spatial memories, but is not necessary for the retrieval or consolidation of emotional memories in general (Thomas et al. 1996). We tested whether this relationship would stand for memories that were appetitive rather than aversive. We tested 20 Dbh-/and 20 Dbh+/mice in an eight-arm radial maze. We found no difference between KOs and controls in ability to recall spatial cues 24 hours after training. This negative result indicated that NE may not be critical for retrieval of all hippocampus-dependent memories but specifically those that are aversive. Using a more standard variation of the above protocol on the radial arm maze, we used this apparatus to test the role of NE in spatial working memory. We found significant, robust differences between Dbh-/and Dbh+/mice after a training period of approximately 14 days. To test whether this difference was due to a potential deficit in acquisition or performance, we restored NE in Dbh-/mice by administering the synthetic precursor L-DOPS after four days of stable behavioral differences between genotypes. In a separate trial, we also restored NE signaling with dexmedetomidine, a selective alpha-2 receptor agonist. A gradual improvement by Dbh-/mice to levels comparable to Dbh+/mice indicated that NE is critical for the acquisition of spatial working memory, and suggested a role for the alpha-2 adrenergic receptor in the processing of spatial working memory.