The Utility of ¹¹C-Arachidonate PET to Study in vivo Dopaminergic Neurotransmission in Humans

Abstract

We developed a novel method to study dopaminergic neurotransmission using positron emission tomography (PET) with [1-(11)C]arachidonic acid ([1-(11)C]AA). Previous preclinical studies have shown the utility of [1-(11)C]AA as a marker of signal transduction coupled to cytosolic phospholipase A(2) (cPLA(2)). Using [1-(11)C]AA and [(15)O]water PET, we measured regional incorporation coefficients K(*) for AA and regional cerebral blood flow (rCBF), respectively, in healthy male volunteers given the D(1)/D(2) agonist (10 or 20 μg/kg subcutaneous) apomorphine. We confirmed a robust central dopaminergic response to apomorphine by observing significant increases in the serum concentration of growth hormone. We observed significant increases, as well as decreases in K(*) and increases in rCBF in response to apomorphine. These changes remained significant after covarying for handedness and apomorphine dosage. The magnitude of increases in K(*) was lower than those in our previous animal experiments, likely reflecting the smaller dose of apomorphine used in the current human study. Changes in K(*) may reflect neuronal signaling downstream of activated D(2)-like receptors coupled to cPLA(2). Changes in rCBF are consistent with previous studies showing net functional effects of D(1)/D(2) activation. [1-(11)C]AA PET may be useful for studying disturbances of dopaminergic neurotransmission in conditions such as Parkinson's disease and schizophrenia.

Imaging brain signal transduction and metabolism via arachidonic and docosahexaenoic acid in animals and humans

“…The increased baseline elevations of k * and increased responsiveness to quinpirole in the lesioned hemisphere are consistent with their higher D 2 -receptor (Ichise et al, 1999), COX-2 protein and cPLA 2 activity and protein levels (Lee et al, 2010), whereas the reduced responsiveness to D-amphetamine is consistent with dropout of presynaptic elements containing the DAT (Ribeiro et al, 2002). Thus, in vivo imaging of AA signaling using dopaminergic drugs can identify pre- and postsynaptic dopaminergic changes in animal models of Parkinson’s disease or other dopaminergic dysfunctions, and possibly in humans with PET (see below) (Thambisetty et al, In Press). …”

“…Since AA signaling can be coupled to D 2 -like receptor initiated AA hydrolysis from phospholipids by cPLA 2 (Nilsson et al, 1998; Vial and Piomelli, 1995) (see 2.1 Receptors coupled to PLA 2 by G-proteins) and the D 1 /D 2 agonist apomorphine stimulated rat brain AA signaling via D 2 -like receptors (the signal could be blocked by the selective D 2 antagonist raclopride) (Bhattacharjee et al, 2008b), we measured rCBF followed by AA signaling using PET in 12 healthy volunteers given vehicle followed by apomorphine (Thambisetty et al, In Press). We observed widespread increases as well as decreases in k*, and increments in rCBF in response to apomorphine.…”

Threshold changes in rat brain docosahexaenoic acid incorporation and concentration following graded reductions in dietary alpha-linolenic acid

“…Brain membrane phospholipids are highly enriched with the polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA, 20:4n-6), which participate in neurotransmission [1, 2], gene transcription and the regulation of brain immunity [3–5]. The brain derives most of its DHA and AA from the plasma unesterified fatty acid pool, which is maintained by liver synthesis-secretion of DHA and AA from their dietary precursors, alpha-linolenic acid (α-LNA, 18:3n-3) and linoleic acid (LA, 18:2n-6), respectively, or from direct dietary incorporation [6–9].…”

Investigation of the Brain Biodistribution of the Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitor [18F]GSK2647544 in Healthy Male Subjects

“…There are limited reports relating to the molecular imaging of lipid-related metabolism in the brain, one such example is the C-11 labelled form of arachidonic acid (AA) that has been used in man to investigate dopaminergic neurotransmission [21] and neuroinflammation [22]. AA is a polyunsaturated fatty acid that is found incorporated high concentrations in brain phospholipids and the metabolism of AA and its oxidatively modified form, F2-isoprostane, has been linked with cPLA 2 and Lp-PLA 2 , respectively [23, 24].…”