The Dopamine D5 Receptor Is Involved in Working Memory

Pharmacological studies indicate that dopamine D(1)-like receptors (D(1) and D(5)) are critically involved in cognitive function. However, the lack of pharmacological ligands selective for either the D(1) or D(5) receptors has made it difficult to determine the unique contributions of the D(1)-like family members. To circumvent these pharmacological limitations, we used D(5) receptor homozygous (-/-) and heterozygous (+/-) knockout mice, to identify the specific role of this receptor in higher order cognitive functions. We identified a novel role for D(5) receptors in the regulation of spatial working memory and temporal order memory function. The D(5) mutant mice acquired a discrete paired-trial variable-delay T-maze task at normal rates. However, both [Formula: see text] and [Formula: see text] mice exhibited impaired performance compared to [Formula: see text] littermates when a higher burden on working memory faculties was imposed. In a temporal order object recognition task, [Formula: see text] exhibited significant memory deficits. No D(5)-dependent differences in locomotor functions and interest in exploring objects were evident. Molecular biomarkers of dopaminergic functions within the prefrontal cortex (PFC) revealed a selective gene-dose effect on Akt phosphorylation at Ser473 with increased levels in [Formula: see text] knockout mice. A trend toward reduced levels in CaMKKbeta brain-specific band (64 kDa) in [Formula: see text] compared to [Formula: see text] was also evident. These findings highlight a previously unidentified role for D(5) receptors in working memory function and associated molecular signatures within the PFC.