Reciprocal cross-sensitization of D1 and D3 receptors following pharmacological stimulation in the hemiparkinsonian rat.

In the majority of Parkinson's disease (PD) patients, long-term dopamine (DA) replacement therapy leads to dyskinesia characterized by abnormal involuntary movements (AIMs). There are various mechanisms of dyskinesia, such as the sensitization of striatal DA D1 receptors (DR) and upregulation of DA D3 receptors (DR). These receptors interact physically and functionally in DR-bearing medium spiny neurons to synergistically drive dyskinesia. However, the cross-receptor-mediated effects due to DR-DR cooperativity are still poorly understood. In pursuit of this, we examined whether or not pharmacological DR or DR stimulation sensitizes the dyskinetic response to the appositional agonist, a process known as cross-sensitization. First, we established DR-DR behavioral synergy in a cohort of 6-OHDA-lesioned female adult Sprague-Dawley rats. Then, in a new cohort, we tested for cross-sensitization in a between-subject design. Five groups received a sub-chronic regimen of either saline, the DR agonist SKF38393 (1.0 mg/kg), or the DR agonist PD128907 (0.3 mg/kg). For the final injection, each group received an acute injection of the other agonist. AIMs were monitored following each injection. Sub-chronic administration of both SKF38393 and PD128907 induced the development of dyskinesia. More importantly, cross-agonism tests revealed reciprocal cross-sensitization; chronic treatment with either SKF38393 or PD128907 induced sensitization to a single administration of the other agonist. This reciprocity was not marked by changes to either DR or DR striatal mRNA expression. The current study provides key behavioral data demonstrating the role of D3R in dyskinesia and provides behavioral evidence of D1R and D3R functional interactions.