A single dose of methamphetamine rescues the blunted dopamine D(1)-receptor activity in the neocortex of D(2)- and D(3)-receptor knockout mice.

Abstract

Knockout mice deficient for dopamine D(2) and D(3) receptors exhibit blunted c-fos responses to D(1)-agonist stimulation. A single dose of methamphetamine (METH), however, leads to a long-term reversal of these blunted c-fos responses in both mutants, and the same effect is obtained with a single administration of a full D(1)-agonist. Consistent with the predominant c-fos expression in the neocortex induced by METH itself, METH pretreatment leads to the largest D(1)-agonist-stimulated c-fos responses in the neocortex of these mutants. For example, a pronounced blunting of neocortical c-fos responses is detected in the prefrontal cortex, a region in which D(1) receptors play a critical role in working memory. METH pretreated mutants, however, exhibit robust c-fos responses in this region that are indistinguishable from wild type. Recent studies indicate that different mechanisms operate in brains of D(2) and D(3) mutants to lead to decreased D(1)-receptor activity. For example, drug-naive D(2), but not D(3), mutants show significantly decreased G protein activation in response to D(1)-agonist stimulation, and METH pretreatment also rescues this abnormal molecular phenotype. Moreover, although the protein phosphatases (PP) 1/2A and 2B play a critical role in modulating G protein activation in wild type, their effect is either diminished (PP1/2A) or abolished (2B) in D(2) mutants. Interestingly however, METH pretreatment does not rescue the activities of these phosphatases in the mutants, suggesting that the long-term effects of a single dose of METH are mediated via effector systems that act downstream of G protein activation.