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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
Author(s) -
SCHMAUSS CLAUDIA,
GLICKSTEIN SARA B.,
ADLERSBERG MELLA,
HSIUNG SHUCHI,
TAMIR HADASSAH
Publication year - 2002
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2002.tb04148.x
Subject(s) - methamphetamine , agonist , neocortex , meth , receptor , chemistry , stimulation , dopamine , endocrinology , knockout mouse , medicine , mutant , neuroscience , biology , pharmacology , biochemistry , gene , monomer , organic chemistry , acrylate , polymer
A bstract : 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.