Mice lacking dopamine D2 and D3 receptors have spatial working memory deficits

Area of Science:

• Neuroscience
• Pharmacology
• Cognitive Science

Background:

• Dopamine receptors, particularly D(1), D(2), and D(3), play crucial roles in prefrontal cortex function.
• Spatial working memory relies on optimal prefrontal cortical dopamine receptor activation.

Purpose of the Study:

• To investigate the role of dopamine D(2) and D(3) receptors in D(1) receptor-mediated responses and spatial working memory.
• To examine the effects of methamphetamine (METH) pretreatment on these functions in receptor-deficient mice.

Main Methods:

• Utilized genetically modified mice lacking dopamine D(2) and/or D(3) receptors.
• Assessed neuronal activation via Fos immunoreactivity following D(1) agonist stimulation.
• Evaluated spatial working memory using a delayed alternation task.
• Investigated the impact of single, low-dose METH pretreatment.

Main Results:

• Dopamine D(2) and D(3) receptor-deficient mice displayed blunted c-fos responses to D(1) agonist stimulation, particularly in the medial prefrontal cortex.
• These mutants also showed significant deficits in spatial working memory.
• METH pretreatment normalized c-fos responses in D(2) mutants and rescued their spatial working memory deficits.
• METH pretreatment had a less pronounced effect on D(3) mutants' c-fos responses and no effect on their working memory.

Conclusions:

• Dopamine D(2) receptors are critical for mediating D(1) receptor-driven neuronal activity and spatial working memory.
• Methamphetamine-induced improvements in spatial working memory in D(2) receptor-deficient mice are linked to D(1) receptor-mediated mechanisms.