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

The polyunsaturated fatty acids (PUFAs), arachidonic acid (AA, 20:4n−6) and docosahexaenoic acid (DHA, 22:6n−3), important second messengers in brain, are released from membrane phospholipid following receptor-mediated activation of specific phospholipase A2 (PLA2) enzymes. We developed an in vivo method in rodents using quantitative autoradiography to image PUFA incorporation into brain from plasma, and showed that their incorporation rates equal their rates of metabolic consumption by brain. Thus, quantitative imaging of unesterified plasma AA or DHA incorporation into brain can be used as a biomarker of brain PUFA metabolism and neurotransmission. We have employed our method to image and quantify effects of mood stabilizers on brain AA/DHA incorporation during neurotransmission by muscarinic M1,3,5, serotonergic 5-HT2A/2C, dopaminergic D2-like (D2, D3, D4) or glutamatergic N-methyl-d-aspartic acid (NMDA) receptors, and effects of inhibition of acetylcholinesterase, of selective serotonin and dopamine reuptake transporter inhibitors, of neuroinflammation (HIV-1 and lipopolysaccharide) and excitotoxicity, and in genetically modified rodents. The method has been extended for the use with positron emission tomography (PET), and can be employed to determine how human brain AA/DHA signaling and consumption are influenced by diet, aging, disease and genetics.

► The arachidonic (AA) and docosahexaenoic (DHA) acids are released from phospholipid.
► We developed an in vivo method in rodents using quantitative autoradiography.
► We imaged regional brain AA and DHA signaling and metabolism during neurotransmission.
► We imaged the effects of mood stabilizers and neuroinflammation on AA metabolism.
► The method can be extended for the use with positron emission tomography in humans.