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 (D 1 R) and upregulation of DA D3 receptors (D 3 R). These receptors interact physically and functionally in D 1 R-bearing medium spiny neurons to synergistically drive dyskinesia. However, the cross-receptor-mediated effects due to D 1 R-D 3 R cooperativity are still poorly understood. In pursuit of this, we examined whether or not pharmacological D 1 R or D 3 R stimulation sensitizes the dyskinetic response to the appositional agonist, a process known as cross-sensitization. First, we established D 1 R-D 3 R 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 D 1 R agonist SKF38393 (1.0 mg/kg), or the D 3 R 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 D 1 R or D 3 R 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.