Reversal of supersensitive striatal dopamine D1 receptor signaling and extracellular signal-regulated kinase activity in dopamine-deficient mice

Lesions of dopaminergic nigrostriatal neurons cause supersensitivity to dopamine in the striatum. Previous work has shown that such supersensitivity, an important aspect of rodent models of Parkinson's disease, is associated with anatomically abnormal patterns in the activation of extracellular signal-regulated kinase. After lesions of dopaminergic neurons, dopamine D-1-receptor agonists activate extracellular signal-regulated kinase in the dorsal striaturn, something not observed in intact animals. Here we used a more selective method of dopamine depletion. Dopamine-deficient mice, in which the tyrosine hydroxylase gene is specifically inactivated in dopaminergic neurons, were used to investigate dopamine D-1-receptor-mediated activation of extracellular signal-regulated kinase. In wild-type mice, acute treatment with a dopamine D,-receptor agonist results in activation of extracellular signal-regulated kinase in the nucleus accumbens without activation in the dorsal striaturn. In contrast, in dopamine-deficient mice, dopamine D-1-receptor-agonist treatment results in activation of extracellular signal-regulated kinase not only in the nucleus accumbens, but also throughout most of the dorsal striaturn. Chronic replacement of dopamine by repeated injection of L-DOPA for 36 h reverses this supersensitive extracellular signal-regulated kinase activation. This reversal displays a dorsal to ventral progression such that, by 36 h, extracellular signal-regulated kinase activation is virtually restricted to the nucleus accumbens, as in wild-type mice. The reversal of dopamine D-1-receptor activation of extracellular signal-regulated kinase in dopamine-deficient mice following chronic L-DOPA treatment shows that the lack of dopamine, rather than absence of other factors secreted from dopaminergic neurons, is responsible for dopamine supersensitivity. (c) 2005 Published by Elsevier Ltd on behalf of IBRO.