A single dose of methamphetamine leads to a long term reversal of the blunted dopamine D1 receptor-mediated neocortical c-fos responses in mice deficient for D2 and D3 receptors.
Dopamine D(1) receptors play an essential role in the induction of expression of the immediate-early gene c-fos in response to pharmacological stimuli. In the forebrain of wild-type mice, administration of a D(1) receptor agonist leads to c-fos mRNA expression levels that are substantially higher than corresponding levels expressed after indirect stimulation of dopamine receptors with methamphetamine. In mice deficient for D(2) and D(3) receptors, c-fos mRNA levels expressed in response to D(1) agonist administration are significantly blunted. However, a single dose of methamphetamine (5 mg/kg) leads to a long lasting reversal of the blunted c-fos responses in these mutants. In the forebrain, this reversal is restricted to the neocortex. Moreover, methamphetamine also enhances c-fos expression levels in preadolescent wild-type mice that normally express low c-fos mRNA in response to D(1) agonist stimulation. Thus, a single dose of methamphetamine leads to a long term increase in D(1) receptor-dependent c-fos responses in brains with either low (preadolescent mice) or blunted (adult D(2) and D(3) mutant mice) c-fos expression levels. A similar long term reversal of the blunted c-fos responses is achieved with a single dose of a full D(1) agonist. These results indicate that the constitutive inactivation of D(2) and D(3) receptors leads to a decrease in agonist-promoted D(1) receptor activity that can be reversed by intermittent agonist stimulation.
Schmauss
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Department of Psychiatry and Neuroscience, Columbia University and New York State Psychiatric Institute, New York, New York 10032, USA. schmauss@neuron.cpmc.columbia.edu
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D016762:Genes, fos / Q000187:drug effects; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D019579:Neocortex / Q000187:drug effects / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050637:Receptors, Dopamine D3; D014158:Transcription, Genetic / Q000187:drug effects*
D001552:Benzazepines; D018491:Dopamine Agonists; C493594:Drd3 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D008694:Methamphetamine; C071262:SK&F 82958