Striatal phosphodiesterase 10A availability is altered secondary to chronic changes in dopamine neurotransmission

Background: Phosphodiesterase 10A (PDE10A) is an important regulator of nigrostriatal dopamine (DA) neurotransmission. However, little is known on the effect of alterations in DA neurotransmission on PDE10A availability. Here, we used [¹⁸F]JNJ42259152 PET to measure changes in PDE10A availability, secondary to pharmacological alterations in DA release and to investigate whether these are D₁- or D₂-receptor driven.

Results: Acute treatment of rats using D-amphetamine (5 mg, s.c. and 1 mg/kg i.v.) did not result in a significant change in PDE10A BP_ND compared to baseline conditions. 5-day D-amphetamine treatment (5 mg/kg, s.c.) increased striatal PDE10A BP_ND compared to the baseline (+24 %, p = 0.03). Treatment with the selective D2 antagonist SCH23390 (1 mg/kg) and D-amphetamine decreased PDE10A binding (-22 %, p = 0.03). Treatment with only SCH23390 further decreased PDE10A binding (-26 %, p = 0.03). No significant alterations in PDE10A mRNA levels were observed.

Conclusions: Repeated D-amphetamine treatment significantly increased PDE10A binding, which is not observed upon selective D₁ receptor blocking. This study suggests a potential pharmacological interaction between PDE10A enzymes and drugs modifying DA neurotransmission. Therefore, PDE10A binding in patients with neuropsychiatric disorders might be modulated by chronic DA-related treatment.