AUTHOR=Carr Gregory V. , Maltese Federica , Sibley David R. , Weinberger Daniel R. , Papaleo Francesco 

TITLE=The Dopamine D5 Receptor Is Involved in Working Memory

JOURNAL=Frontiers in Pharmacology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2017.00666

DOI=10.3389/fphar.2017.00666

ISSN=1663-9812

ABSTRACT=<p>Pharmacological studies indicate that dopamine D<sub>1</sub>-like receptors (D<sub>1</sub> and D<sub>5</sub>) are critically involved in cognitive function. However, the lack of pharmacological ligands selective for either the D<sub>1</sub> or D<sub>5</sub> receptors has made it difficult to determine the unique contributions of the D<sub>1</sub>-like family members. To circumvent these pharmacological limitations, we used D<sub>5</sub> 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<sub>5</sub> receptors in the regulation of spatial working memory and temporal order memory function. The D<sub>5</sub> mutant mice acquired a discrete paired-trial variable-delay T-maze task at normal rates. However, both <inline-formula><mml:math id="M1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mi mathvariant="normal" mathcolor="black">D</mml:mi><mml:mi mathvariant="normal" mathcolor="black">5</mml:mi><mml:mn mathvariant="normal" mathcolor="black">+/-</mml:mn></mml:msubsup></mml:math></inline-formula> and <inline-formula><mml:math id="M28" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mi mathvariant="normal" mathcolor="black">D</mml:mi><mml:mi mathvariant="normal" mathcolor="black">5</mml:mi><mml:mn mathvariant="normal" mathcolor="black">-/-</mml:mn></mml:msubsup></mml:math></inline-formula> mice exhibited impaired performance compared to <inline-formula><mml:math id="M59" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mi mathvariant="normal" mathcolor="black">D</mml:mi><mml:mi mathvariant="normal" mathcolor="black">5</mml:mi><mml:mn mathvariant="normal" mathcolor="black">+/+</mml:mn></mml:msubsup></mml:math></inline-formula> littermates when a higher burden on working memory faculties was imposed. In a temporal order object recognition task, <inline-formula><mml:math id="M2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mi mathvariant="normal" mathcolor="black">D</mml:mi><mml:mi mathvariant="normal" mathcolor="black">5</mml:mi><mml:mn mathvariant="normal" mathcolor="black">+/-</mml:mn></mml:msubsup></mml:math></inline-formula> exhibited significant memory deficits. No D<sub>5</sub>-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 <inline-formula><mml:math id="M29" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mi mathvariant="normal" mathcolor="black">D</mml:mi><mml:mi mathvariant="normal" mathcolor="black">5</mml:mi><mml:mn mathvariant="normal" mathcolor="black">-/-</mml:mn></mml:msubsup></mml:math></inline-formula> knockout mice. A trend toward reduced levels in CaMKKbeta brain-specific band (64 kDa) in <inline-formula><mml:math id="M30" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mi mathvariant="normal" mathcolor="black">D</mml:mi><mml:mi mathvariant="normal" mathcolor="black">5</mml:mi><mml:mn mathvariant="normal" mathcolor="black">-/-</mml:mn></mml:msubsup></mml:math></inline-formula> compared to <inline-formula><mml:math id="M60" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mi mathvariant="normal" mathcolor="black">D</mml:mi><mml:mi mathvariant="normal" mathcolor="black">5</mml:mi><mml:mn mathvariant="normal" mathcolor="black">+/+</mml:mn></mml:msubsup></mml:math></inline-formula> was also evident. These findings highlight a previously unidentified role for D<sub>5</sub> receptors in working memory function and associated molecular signatures within the PFC.</p>