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

Mice deficient for dopamine D(2) and D(3) receptors exhibit blunted c-fos responses to D(1) 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 D(1) 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 D(2) mutants but remained submaximal in METH-pretreated D(3) 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 D(1) receptors by synaptically released dopamine. Both D(2) and D(3) mutants exhibited deficits in their spatial working memory, with increasing impairments at increasing delays. Whereas METH pretreatment rescued the spatial working memory of D(2) mutants, it had no effect on D(3) mutants. These data suggest that the sustained improvement of spatial working memory in METH-pretreated D(2) mutants is attributable to D(1) receptor-mediated mechanisms.