PET measurement of dopamine D2 receptor-mediated changes in striatopallidal function

Abstract

This study was designed to validate an in vivo measurement of the functional sensitivity of basal ganglia neuronal circuits containing dopamine D2 receptors. We hypothesized that a D2 agonist would decrease striatopallidal neuronal activity, and hence regional cerebral blood flow (rCBF) over the axon terminals in the globus pallidus. Quantitative pallidal blood flow was measured using positron emission tomography (PET) with bolus injections of H215O and arterial sampling in six baboons before and after intravenous administration of the selective D2 agonist U91356a. We also tested whether the response to U91356a was modified by previous acute administration of various antagonists. Another baboon had serial measurements of blood flow under identical conditions, but received no dopaminergic drugs. In all animals that received U91356a, pallidal flow decreased in a dose-related manner. Global CBF had a similar response, but the decline in pallidal flow was greater in magnitude and remained significant after accounting for the global effect. A D2 antagonist, but not antagonists of D1, serotonin-2, or peripheral D2 receptors, prevented this decrease. This work demonstrates and validates an in vivo measure of the sensitivity of D2-mediated basal ganglia pathways. It also supports the hypothesis that activation of the indirect striatopallidal pathway, previously demonstrated using nonselective D2-like agonists, can be mediated specifically by D2 receptors. We speculate that the U91356a-PET technique may prove useful in detecting functional abnormalities of D2-mediated dopaminergic function in diseases such as parkinsonism, dystonia, Tourette syndrome, or schizophrenia.

Fig. 1.

The Davis and Huffman (1968) atlas points used for GP, as transferred to a representative MRI and matching PET image. Each PET image was sampled using a ball-shaped volume of interest with radius 5 mm, centered on the points indicated. (See Materials and Methods).

Fig. 2.

U91356a causes a dose-dependent decrease in GP rCBF. Mean (± SEM) values for blood flow in the GP are shown at baseline and after acute intravenous administration of low, medium, and high doses of the D₂ agonist U91356a. Key to doses: low = 1 to 2 μg/kg, medium = 10 to 22 μg/kg, and high = 100 to 220 μg/kg.

Fig. 3.

GP rCBF response to U91356a relative to global or cerebellar rCBF. Mean values for relative GP blood flow are graphed at baseline and after different doses of the D₂agonist U91356a. In the top graph, absolute GP rCBF was normalized by setting global CBF to 50. In the bottom graph, cerebellum CBF was used rather than global CBF.

Fig. 4.

Effect of pretreatment with various antagonists on the GP rCBF response to U91356a. In each graph, control experiments (mean ± SEM) are represented by filled circles and antagonist pretreatment experiments are represented by hollow squares. Top left, eticlopride (D₂antagonist, 4 mg/kg); top right, SCH23390 (D₁ antagonist, 1 mg/kg); bottom left, ketanserin (5HT2 antagonist, 0.6 mg/kg); bottom right, domperidone (peripheral D₂ antagonist, 0.1 mg/kg).