IN VIVO IMAGING OF 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 PLA2 enzymes. We developed an in vivo method in rodents using quantitative autoradiography to image PUFA incorporation into brain from plasma, and showed that AA and DHA incorporation rates equal their rates of metabolic consumption by brain. We employed our in vivo imaging method in rodents to demonstrate signaling effects of mood stabilizers on brain AA/DHA incorporation during neurotransmission by muscarinic M(1,3,5), serotonergic 5-HT(2A/2C), dopaminergic D(2)-like (D(2), D(3), D(4)) 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. (1).(4) KNOCKING OUT THE DOPAMINE REUPTAKE TRANSPORTER (DAT) DOES NOT CHANGE THE BASELINE BRAIN ARACHIDONIC ACID SIGNAL IN THE MOUSE. Dopamine transporter (DAT) homozygous knockout (DAT(-/-)) mice have a 10-fold higher extracellular (DA) concentration in the caudate-putamen and nucleus accumbens than do wildtype (DAT(+/+)) mice, but show reduced presynaptic DA synthesis and fewer postsynaptic D(2) receptors. One aspect of neurotransmission involves DA binding to postsynaptic D(2)-like receptors coupled to cytosolic phospholipase A(2) (cPLA(2)), which releases the second messenger, arachidonic acid (AA), from synaptic membrane phospholipid. We hypothesized that tonic overactivation of D(2)-like receptors in DAT(-/-) mice due to the excess DA would not increase brain AA signaling, because of compensatory downregulation of postsynaptic DA signaling mechanisms, and confirmed this hypothesis with our in vivo imaging method in DAT(-/-), DAT(+/-), and DAT(+/+) mice. These results differ from reported increases AA signaling and brain cPLA(2) expression, in serotonin reuptake transporter (5-HTT) knockout mice, and suggest that postsynaptic dopaminergic neurotransmission mechanisms involving AA are downregulated despite elevated DA in DAT(-/-) mice. (2) TRANSLATIONAL STUDIES ON REGULATION OF BRAIN DOCOSAHEXAENOIC ACID (DHA) METABOLISM IN VIVO. One goal in the field of brain polyunsaturated fatty acid (PUFA) metabolism is to translate studies conducted in vitro and in animal models to the clinical setting. Doing so should elucidate the role of PUFAs in the human brain, and effects of diet, drugs, disease and genetics on this role. In a review, we discussed new in vivo radiotracer kinetic and neuroimaging techniques that allow us to do this, with a focus on docosahexaenoic acid (DHA). We illustrated how brain PUFA metabolism is influenced by graded reductions in dietary n-3 PUFA content in unanesthetized rats, and how kinetic tracer techniques in rodents have helped to identify mechanisms of action of mood stabilizers used in bipolar disorder, how DHA participates in neurotransmission, and how brain DHA metabolism is regulated by calcium-independent iPLA(2)beta. In humans, regional rates of brain DHA metabolism can be quantitatively imaged with positron emission tomography following intravenous injection of 1-(11)CDHA. (3)
Showing the most recent 10 out of 18 publications
