The Dopamine D5 Receptor Is Involved in Working Memory.

Pharmacological studies indicate that dopamine D-like receptors (D and D) are critically involved in cognitive function. However, the lack of pharmacological ligands selective for either the D or D receptors has made it difficult to determine the unique contributions of the D-like family members. To circumvent these pharmacological limitations, we used D 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 receptors in the regulation of spatial working memory and temporal order memory function. The D 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-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 receptors in working memory function and associated molecular signatures within the PFC.