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.
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.
Schmauss
Claudia
C
Department of Psychiatry, Columbia University College of Physicians & Surgeons, New York, New York 10032, USA. schmauss@neuron.cpmc.columbia.edu
Glickstein
Sara B
SB
Adlersberg
Mella
M
Hsiung
Shi-Chi
SC
Tamir
Hadassah
H
D000818:Animals; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D016762:Genes, fos / Q000187:drug effects / Q000502:physiology; D017403:In Situ Hybridization; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019579:Neocortex / Q000187:drug effects / Q000502:physiology*; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050637:Receptors, Dopamine D3
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; C493594:Drd3 protein, mouse; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D008694:Methamphetamine