PET Measurement of Dopamine D₂Receptor-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 D 2 receptors. We hypothesized that a D 2 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 H 2 15 O and arterial sampling in six baboons before and after intravenous administration of the selective D 2 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 D 2 antagonist, but not antagonists of D 1 , serotonin-2, or peripheral D 2 receptors, prevented this decrease. This work demonstrates and validates an in vivo measure of the sensitivity of D 2 -mediated basal ganglia pathways. It also supports the hypothesis that activation of the indirect striatopallidal pathway, previously demonstrated using nonselective D 2 -like agonists, can be mediated specifically by D 2 receptors. We speculate that the U91356a-PET technique may prove useful in detecting functional abnormalities of D 2 -mediated dopaminergic function in diseases such as parkinsonism, dystonia, Tourette syndrome, or schizophrenia.

Dopaminergic modulation of response inhibition: an fMRI study

“…Levodopa decreased rCBF in Parkinson's disease patients and normal controls [38], and, in a nonhuman primate model, inferior parietal regions showed decreased rCBF after acute doses of D1-or D3-preferring dopamine agonists [12,15]. The cerebellum has few dopamine receptors, but it has long been known to change its metabolic activity after a dopaminergic challenge [11,51]. Additionally, the cerebellum receives minor dopaminergic innervation from the ventral tegmental area [40].…”

A mechanistic account of striatal dopamine function in human cognition: Psychopharmacological studies with cabergoline and haloperidol.

“…Supporting this notion, D 2 receptor blockade (simulating a lack of D 2 stimulation during dips) is associated with enhanced No-Go (indirect pathway) activity and associated increases in corticostriatal longterm potentiation (Calabresi et al, 1997;Centonze et al, 2004;Finch, 1999;Robertson, Vincent, & Fibiger, 1992), whereas D 2 stimulation inhibits No-Go activity (Black, Gado, & Perlmutter, 1997) and decreases synaptic strength (Calabresi et al, 1997).…”

Commentary: Dopaminergic dysfunction in DYT1 dystonia

“…Further evidence that altered dopaminergic transmission plays a role in dystonia comes from PET imaging studies, which have demonstrated abnormalities of dopaminergic transmission in many dystonia patients (Ernst et al, 1996;Wong et al, 1996;Black et al, 1997;Perlmutter et al, 1997a,b;Brashear et al, 1999;Perlmutter and Mink, 2004). Specifically, reduced striatal dopamine receptor binding (Perlmutter et al, 1997a,b;Naumann et al, 1998), or [ 18 F]-DOPA uptake, suggestive of reduced DOPA decarboxylase activity (Playford et al, 1993), have been observed.…”