Differential regulation of the dopamine D1, D2 and D3 receptor gene expression and changes in the phenotype of the striatal neurons in mice lacking the dopamine transporter

Mice with a genetic disruption of the dopamine transporter (DAT(-/-)) exhib it locomotor hyperactivity and profound alterations in the homeostasis of t he nigrostriatal system, e.g. a dramatic increase in the extracellular dopa mine level. Here, we investigated the adaptive changes in dopamine D1, D2 a nd D3 receptor gene expression in the caudate putamen and nucleus accumbens of DAT(-/-) mice. We used quantitative in situ hybridization and found tha t the constitutive hyperdopaminergia results in opposite regulations in the gene expression for the dopamine receptors, In DAT(-/-) mice, we observed increased mRNA levels encoding the D3 receptor (caudate putamen, +60-85%; n ucleus accumbens, +40-107%), and decreased mRNA levels for both D1 (caudate putamen, -34%; nucleus accumbens, -45%) and D2 receptors (caudate putamen, -36%; nucleus accumbens, -33%). Furthermore, we assessed the phenotypical organization of the striatal efferent neurons by using double in situ hybri dization. Our results show that in DAT(+/+) mice, D1 and D2 receptor mRNAs are segregated in two different main populations corresponding to substance P and preproenkephalin A mRNA-containing neurons, respectively. The phenot ype of D1 or D2 mRNA-containing neurons was unchanged in both the caudate p utamen and nucleus accumbens of DAT(-/-) mice. Interestingly, we found an i ncreased density of preproenkephalin A-negative neurons that express the D3 receptor mRNA in the nucleus accumbens (core, +35%; shell, +46%) of DAT(-/ -) mice. Our data further support the critical role for the D3 receptor in the regulation of D1-D2 interactions, an action being restricted to neurons coexpressing D1 and D3 receptors in the nucleus accumbens.