Imaging Brain Signal Transduction In Vivo With Radiolabeled Arachidonic Acid

National Institute On Aging

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Abstract

IMAGING ARACHIDONIC ACID-MEDIATED SIGNALING IN RODENT BRAIN.[unreadable] In rats pretreated with the non-selective cyclooxygenase (COX) inhibitor, flurbiprofen, and in mice in which cyclooxygenase (COX)-2 was genetically knocked out, the cholinergic-receptor initiated brain arachidonic acid (AA) signal, measured with our tracer method, was confirmed to represent AA release from brain membrane phospholipid by phospholipase A2, followed by AA metabolic loss almost entirely through the COX-2 pathway (Basselin et al. 2007).[unreadable] [unreadable] REDUCED ARACHIDONIC ACID SIGNALING BY CHRONIC AMPHETAMINE MAY BE RELATED TO POST-DRUG DEPRESSION IN HUMANS[unreadable] Withdrawal from amphetamine abuse causes depression in drug addicts. In rats, such withdrawal was shown to widely decrease brain AA signaling, an effect that may be related to the post-amphetamine depression noted in humans and in rats (Bhattacharjee et al. 2008a).[unreadable] [unreadable] APOMORPHINE STIMULATES ARACHIDONIC ACID SIGNALING VIA DOPAMINE D2-LIKE RECEPTORS[unreadable] Apomorphine, a mixed dopamine D1/D2 receptor agonist, is used to treat patients with Parkinson disease. In awake rats, acute apomorphine provoked a robust arachidonic acid (AA) signal in brain regions with dopamine receptors solely through the D2 receptors, as the signal could be blocked by pre-administration of raclopride, a D2/D3 receptor antagonist (Bhattacharjee et al. 2008b). This study supports our approved clinical protocol in which apomorphine is injected to image dopamine signaling with positron emission tomography.[unreadable] [unreadable] ELEVATED BRAIN ARACHIDONIC ACID SIGNALING IN SEROTONIN TRANSPORTER (5-HTT) DEFICIENT MICE[unreadable] Certain polymorphisms of the serotonin reuptake transporter (5-HTT) leading to its reduced function increase susceptibility to psychiatric disorders in human subjects. Heterozygous (5-HTT+/-) deficient mice, models for humans with these polymorphisms, had elevated brain serotonin concentrations and behavioral abnormalities. In these mice, baseline arachidonic acid (AA) signaling was elevated, as was brain cytosolic phospholipase A2 activity (which is coupled to post-synaptic serotonin receptors). These results suggest that AA signaling also would be elevated in patients with reduced-function polymorphisms. This could be explored using positron emission tomography.