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.