Dopamine D1 receptor modulation of glutamate receptor messenger RNA levels in the neocortex and neostriatum of unilaterally 6-hydroxydopamine-lesioned rats

Abstract The effect of treatment with the D 1 dopamine receptor agonist SKF 38393 on the expression of metabotropic glutamate receptor 1, 3, 4 and 5 receptor subtypes and of the glutamate N -methyl- d -aspartate ionotropic receptor subunits NR1, NR2A and NR2B was analysed using in situ hybridization. We studied the neocortex and neostriatum of normal rats and of rats treated with 6-hydroxydopamine, a neurotoxin that, after intracerebral injection into the ventral tegmental area, causes selective degeneration of the ascending dopamine pathway. In the 6-hydroxydopamine-lesioned rats, metabotropic glutamate receptor subtype 3 messenger RNA levels were ipsilaterally increased in the neocortex and neostriatum, while the levels of metabotropic glutamate receptor subtype 4 messenger RNA were bilaterally increased in both regions. When administered to the 6-hydroxydopamine-lesioned rats, the D 1 receptor agonist SKF 38393 (3×20 mg/kg, s.c.) produced a bilateral decrease in the expression of the metabotropic glutamate receptor subtype 1 and 5 receptor messenger RNA levels in the neocortex and neostriatum. In the neostriatum, SKF 38393 attenuated the ipsilateral increase in the expression of striatal metabotropic glutamate receptor subtype 3 messenger RNA produced by the 6-hydroxydopamine lesion. Furthermore, SKF 38393 produced a bilateral decrease in the levels of NR1 receptor subunit messenger RNA and, in contrast, an increase in the striatal NR2B messenger RNA levels. All these effects were abolished by the D 1 receptor antagonist SCH 23360. These results indicate a differential D 1 receptor-mediated modulation of the expression of some glutamate receptor subtypes in the neostriatum and neocortex, in agreement with the idea of a functional coupling between dopamine and excitatory amino acid systems in both regions. Thus, pharmacological targeting of excitatory amino acid systems could provide alternative or complementary treatment strategies for diseases involving dopaminergic systems in the striatum (e.g., Parkinson's disease) and cortex (e.g., schizophrenia).