Abstract
BackgroundPhosphodiesterase 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.ResultsAcute 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 BPND compared to baseline conditions. 5-day D-amphetamine treatment (5 mg/kg, s.c.) increased striatal PDE10A BPND 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.ConclusionsRepeated 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.
Highlights
Phosphodiesterase 10A (PDE10A) is an important regulator of nigrostriatal dopamine (DA) neurotransmission
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
Summary
Phosphodiesterase 10A (PDE10A) is an important regulator of nigrostriatal dopamine (DA) neurotransmission. Little is known on the effect of alterations in DA neurotransmission on PDE10A availability. MSNs of the direct pathway are striatonigral neurons that project to the internal part of the globus pallidus and the substantia nigra pars reticularis. The indirect pathway consists of striatopallidal MSNs that project to the external globus pallidus. Activation of the indirect pathway removes the inhibition of the external globus pallidus on the subthalamic nucleus. This increases the inhibition of the globus pallidus and substantia nigra on the thalamus and inhibits behavioral activity (Albin et al 1989)
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