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

Mice deficient for dopamine D₂ and D₃ receptors exhibit blunted c-fos responses to D₁ agonist stimulation. Stereologic cell counting revealed decreased numbers of medial prefrontal cortex neurons that express Fos immunoreactivity in all layers, particularly in the prelimbic and anterior cingulate subregions. Pretreatment of these mutants with a single, low dose of methamphetamine (METH) led to a sustained increase in the number of neurons that express Fos immunoreactivity in response to a D₁ agonist challenge, which was most significant in prelimbic and anterior cingulate subregions. The increased c-fos responses reached wild-type-like levels in METH-pretreated D₂ mutants but remained submaximal in METH-pretreated D₃ mutants. Additional studies tested the performance of wild type and mutants in a delayed alternation test, a cognitive task critically dependent on optimal activation of prefrontal cortical D₁ receptors by synaptically released dopamine. Both D₂ and D₃ mutants exhibited deficits in their spatial working memory, with increasing impairments at increasing delays. Whereas METH pretreatment rescued the spatial working memory of D₂ mutants, it had no effect on D₃ mutants. These data suggest that the sustained improvement of spatial working memory in METH-pretreated D₂ mutants is attributable to D₁ receptor-mediated mechanisms.