Justin Klaff

National Institute on Aging, Baltimore, Maryland, United States

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Publications (4)23.77 Total impact

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    ABSTRACT: Serotonergic 5-HT(2A/2C) receptors can be coupled to phospholipase A(2) (PLA(2)) activation to release the second messenger, arachidonic acid (AA), from membrane phospholipids. We wished to see if this signaling process in rat brain would be altered by chronic administration followed by 3days of washout of the selective serotonin reuptake inhibitor, fluoxetine. We injected [(3)H]AA intravenously in unanesthetized rats and used quantitative autoradiography to determine the incorporation coefficient k() for AA (regional brain radioactivity/integrated plasma radioactivity), a marker of PLA(2) activation, in each of 86 brain regions. k() was measured following acute i.p. saline or (+/-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI, 1.0mg/kg i.p.), a 5-HT(2A/2C) receptor agonist, in rats injected for 21days with 10mg/kg i.p. fluoxetine or saline daily, followed by 3days without injection. Acute DOI produced statistically significant increments in k() in brain regions with high densities of 5-HT(2A/2C) receptors, but the increments did not differ significantly between the chronic fluoxetine- and saline-treated rats. Additionally, chronic fluoxetine compared with saline widely and significantly increased baseline values of k(). These results suggest that 5-HT(2A/2C) receptor-initiated AA signaling is unaffected by chronic fluoxetine plus 3days of washout in the rat, but that baseline AA signaling is nevertheless upregulated. This upregulation likely occurs independently of significant active drug in brain, considering the short brain half-lives of it and its norfluoxetine metabolite. Such upregulation may contribute to fluoxetine's efficacy against human depression.
    European Neuropsychopharmacology 01/2007; 16(8):561-71. · 4.60 Impact Factor
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    ABSTRACT: In vitro studies have shown that 5-HT2 receptors can be coupled via G-proteins to phospholipase A2 (PLA2) activation, releasing arachidonic acid from phospholipids. To examine this signaling pathway in brain, we developed an in vivo method to image regional brain PLA2 activation in unanesthetized rats given different types of serotonergic drugs. Increased arachidonate incorporation from plasma, in response to drug-induced PLA2-activation, can be quantified with autoradiography, following the intravenous injection of radiolabeled arachidonate. For example, a 5-HT(2A/2C) receptor agonist, (+/-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane, produced widespread increases in incorporation of labeled arachidonate by directly binding to 5-HT(2A/2C) receptors. Fluoxetine, a selective serotonin reuptake inhibitor, selectively increased incorporation of arachidonic acid by increasing 5-HT availability in the synaptic cleft and thus indirectly activating phospholipase A2. The detailed method is described.
    Brain Research Protocols 09/2003; 12(1):16-25. · 1.82 Impact Factor
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    ABSTRACT: Fluoxetine, a selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor, is used widely to treat depression and related disorders. By inhibiting presynaptic 5-HT reuptake, fluoxetine is thought to act by increasing 5-HT in the synaptic cleft, thus 5-HT binding to postsynaptic 5-HT(2A/2C) receptors. These receptors can be coupled via a G-protein to phospholipase A(2) (PLA(2)), which when activated releases the second messenger arachidonic acid from synaptic membrane phospholipids. To image this activation, fluoxetine (10 mg/kg) or saline vehicle was administered i.p. to unanesthetized rats, and regional brain incorporation coefficients k(*) of intravenously injected radiolabeled arachidonic acid were measured after 30 min. Compared with vehicle, fluoxetine significantly increased k(*) in prefrontal, motor, somatosensory, and olfactory cortex, as well as in the basal ganglia, hippocampus, and thalamus. Many of these regions demonstrate high densities of the serotonin reuptake transporter and of 5-HT(2A/2C) receptors. Brain stem, spinal cord, and cerebellum, which showed no significant response to fluoxetine, have low densities of the transporters and receptors. The results show that it is possible to image quantitatively PLA(2)-mediated signal transduction in vivo in response to fluoxetine.
    Neuropsychopharmacology 08/2003; 28(7):1219-26. · 8.68 Impact Factor
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    ABSTRACT: Incorporation coefficients k(*) of intravenously injected [(3)H]arachidonic acid from blood into brain reflect the release from phospholipids of arachidonic acid by receptor-initiated activation of phospholipase A(2) (PLA(2)). In unanesthetized adult rats, 2.5 mg/kg intraperitoneally (i.p.) (+/-)2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), which is a 5-HT(2A/2C) receptor agonist, has been reported to produce the behavioral changes of what is known as the 5-HT(2) syndrome, but only a few small regional decrements in brain glucose metabolism. In this study, 2.5 mg/kg i.p. DOI, when administered to unanesthetized rats, produced widespread and significant increases, of the order of 60%, in k(*) for arachidonate, particularly in neocortical brain regions reported to have high densities of 5-HT(2A) receptors. The increases could be entirely blocked by chronic pretreatment with mianserin, a 5-HT(2) receptor antagonist. The results suggest that the 5-HT(2) syndrome involves widespread brain activation of PLA(2) via 5-HT(2A) receptors, leading to the release of the second messenger, arachidonic acid. Chronic mianserin, a 5-HT(2) antagonist, prevents this activation.
    Neuropsychopharmacology 03/2003; 28(2):244-52. · 8.68 Impact Factor