Abstract
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.
Highlights
(adult D2 and D3 mutant mice) c-fos expression levels
This study revealed that the constitutive inactivation of D2 and D3 receptors leads to a decrease in agonist-promoted D1 receptor activity that can be reversed in a long term manner by a single dose of either methamphetamine or a D1 agonist
In five independent experiments, c-fos mRNA levels expressed in D2 mutants were only 12.2 Ϯ 3.7% of the corresponding wild-type levels (p Ͻ 0.001), and c-fos mRNA levels of D3 mutants reached only 15.7 Ϯ 9.4% of levels expressed in wild type (p Ͻ 0.001). c-fos mRNA levels expressed in D2 and D3 mutants did not differ significantly (Table I)
Summary
(adult D2 and D3 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 D1 agonist. The study of Moratalla et al [3] identified anatomically restricted alterations in c-fos responses to haloperidol, a neuroleptic drug that blocks the D2-like dopamine receptor subtypes D2 and D3, and other studies on mice deficient for D3 receptors revealed blunted c-fos responses to D1 agonist stimulation. These responses were even further reduced when D3 mutants were pretreated with the D2-like antagonist eticlopride [4]. Studies on mutant mice have demonstrated that the expression of dopamine D1 receptors is essential for the
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