Antidepressant-Induced Increase in High-Affinity Rolipram Binding Sites in Rat Brain: Dependence on Noradrenergic and Serotonergic Function

Zhao, Yu; Zhang, Han‐Ting; O'Donnell, James M.

doi:10.1124/jpet.103.053215

Cited by 32 publications

(26 citation statements)

References 32 publications

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“…HARBS and the LARBS are more accurately described as two distinct binding-affinity states of the same catalytic site rather than separate sites (Jacobitz et al, 1996). Brain is rich in HARBS, with the percentage varying from 47 to 66% (Zhao et al, 2003). By contrast, only LARBS is detected in peripheral tissues.…”

Section: Discussionmentioning

confidence: 96%

Conversion of Phosphodiesterase-5 (PDE5) Catalytic Site to Higher Affinity by PDE5 Inhibitors

Blount¹,

Zoraghi²,

Bessay³

et al. 2007

J Pharmacol Exp Ther

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Phosphodiesterase-5 (PDE5) specifically hydrolyzes cGMP, thereby contributing to modulation of intracellular levels of this nucleotide. In the present study, preincubation with cGMP increased PDE5 catalytic activity for cGMP degradation, and it converted the PDE5 catalytic site to a form that was more potently inhibited by each of the three PDE5 catalytic sitespecific inhibitors: sildenafil, vardenafil, and tadalafil. These results implied that elevated cGMP initiates a physiological negative feedback on the cGMP pathway by increasing the affinity of the PDE5 catalytic site for cGMP. This increase in catalytic site activity or affinity for inhibitors could be caused by binding of cGMP to either the PDE5 allosteric sites, catalytic site, or both. Whether occupation of the catalytic site alone could mediate the effect was examined using radiolabeled PDE5 inhibitors in the absence of cGMP. Exchange-dissociation H inhibitors converted the biphasic pattern to a single slow (highaffinity) component. Studies of amino-terminally truncated PDE5 established that full-length mammalian GAF-B (cGMP-binding phosphodiesterase, Anabaena adenylyl cyclases, Escherichia coli FhlA) subdomain conjoined with the catalytic domain was sufficient for this conversion. In conclusion, binding of substrate or substrate analogs such as PDE5 inhibitors to the catalytic site converts a fast (low-affinity) inhibitor dissociation component of the PDE5 catalytic site to a slow (high-affinity) inhibitor dissociation component. This effect is predicted to improve the substrate affinity or inhibitory potencies of these compounds in intact cells.

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Section: Discussionmentioning

confidence: 96%

Conversion of Phosphodiesterase-5 (PDE5) Catalytic Site to Higher Affinity by PDE5 Inhibitors

Blount¹,

Zoraghi²,

Bessay³

et al. 2007

J Pharmacol Exp Ther

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“…This has been confirmed using [ 3 H]-3-(cyclopentyloxy)-N-(3,5-dichloropyridin-4-yl)-4-methoxybenzamide (piclamilast), which binds with equal high affinity to the HARBS and LARBS (Zhao et al, 2003a). Although the LARBS is found in both the brain and peripheral tissues, the HARBS is found only in the brain; consistent with this, the HARBS and LARBS mediate distinct pharmacological effects (Saccomano et al, 1991;Barnette et al, 1996;Zhao et al, 2003b).…”

Section: Introductionmentioning

confidence: 62%

“…Previously, it has been found that repeated treatment with the antidepressant drugs desipramine and fluoxetine increases the HARBS in brain, measured either by [ 3 H]rolipram or [ 3 H]piclamilast binding (Zhao et al, 2003b). By contrast, such treatment does not alter the LARBS in brain.…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, such treatment does not alter the LARBS in brain. The effects of fluoxetine and desipramine on the HARBS in the brain are prevented when noradrenergic or serotonergic neurons are lesioned with 6-hydroxydopamine or 5,7-dihydroxytryptamine, respectively (Zhao et al, 2003b). This suggests that the neurochemical pathways involved in the mediation of antidepressant activity can influence PDE4 expression and activity.…”

Section: Discussionmentioning

confidence: 99%

“…It is likely that increased PDE4 expression is a compensatory change in response to increased cAMP signaling that results from antidepressant treatment; prior work demonstrated such regulation of PDE4 in cultured neurons (D'Sa et al, 2002;Hajjhussein et al, 2007). Repeated treatment of rats with antidepressant drugs increases the HARBS, but not the LARBS, in cerebral cortex and hippocampus (Zhao et al, 2003b). Consistent with this finding, comparison of the acute behavioral effects of rolipram, piclamilast, and 4-(2-(3-(cyclopentyloxy)-4-methoxyphenyl)-2-phenylethyl)pyridine (CDP840), PDE4 inhibitors that differ in their interactions with the HARBS and LARBS (Zhao et al, 2003a), suggests a predominant role for the HARBS in mediating acute antidepressant-like effects on behavior (Zhang et al, 2006).…”

Section: Introductionmentioning

confidence: 95%

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Effects of Repeated Treatment with Phosphodiesterase-4 Inhibitors on cAMP Signaling, Hippocampal Cell Proliferation, and Behavior in the Forced-Swim Test

Xiao¹,

O’Callaghan²,

O'Donnell³

2011

J Pharmacol Exp Ther

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The effects of repeated treatment with the phosphodiesterase-4 (PDE4) inhibitors rolipram, piclamilast, and 4-(2-(3-(cyclopentyloxy)-4-methoxyphenyl)-2-phenylethyl)pyridine (CDP840), which differ in their interactions with high-and low-affinity binding conformers of the enzyme, were contrasted to those of acute treatment on cAMP signaling, hippocampal cell proliferation, and immobility in the forced-swim test in rats. Repeated treatment with rolipram (1 and 3 mg/kg), piclamilast (0.3 and 1 mg/kg), or CDP840 (10 and 30 mg/kg) for 16 days increased cAMP and phosphorylation of cAMP response element binding protein (pCREB) in hippocampus and prefrontal cortex. In addition, repeated treatment with the PDE4 inhibitors increased proliferation and survival of newborn cells in the hippocampus and produced antidepressant-like effects on behavior, as evidenced by decreased immobility in the forced-swim test. Acute treatment with rolipram (3 mg/kg), piclamilast (1 mg/kg), or CDP840 (30 mg/kg) induced transient increases in cAMP and pCREB in hippocampus and prefrontal cortex, but the dose and time dependence of these effects did not parallel the behavioral effects. Compared with rolipram and piclamilast, repeated treatment with CDP840 exerted lesser effects on neural and behavioral measures, probably because of its weak interaction with the high-affinity binding conformer of PDE4. This suggests the relative importance of the high-affinity binding conformer in the mediation of the long-term effects of PDE4 inhibition on cAMP/pCREB signaling, hippocampal cell proliferation, and antidepressant-like effects on behavior.

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In vivo and in vitro measurement of brain phosphodiesterase 4 in rats after antidepressant administration

Fujita

Imaizumi

D’Sa

et al. 2006

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Based largely on in vitro measurements, the mechanism of several antidepressant treatments is thought to involve upregulation of 3'-5'-cyclic adenosine monophosphate (cAMP) signal transduction cascade and a corresponding increase in phosphodiesterase (PDE) 4, the enzyme that metabolizes cAMP. To assess the in vivo status of PDE4, rats were chronically treated with imipramine and then studied with: (1) in vivo positron emission tomography (PET) measurement of (R)-[(11)C]rolipram binding, (2) in vitro measurement of [(3)H]rolipram binding in brain homogenates, and (3) Western blotting for protein levels of PDE4 isoforms. Imipramine administration caused no significant change in B(max)/K(d), for both in vivo measurements with (R)-[(11)C]rolipram and in vitro measurements with [(3)H]rolipram in frontal cortex, hippocampus, and diencephalon. None of 10 isoforms of PDE4A, B, and D measured with immunoblots of frontal cortex and hippocampus showed a significant change. In summary, using relatively large brain regions for both in vivo imaging and in vitro measures of radiolabeled ligand binding and protein levels, chronic imipramine treatment via continuous mini-pump administration caused no significant change in PDE4 levels. Most, but not all, prior in vitro studies have found increased PDE4 levels after antidepressant administration. The current results raise questions about the in vivo effects of antidepressant treatment on PDE4 and on other potentially important experimental factors (e.g., continuous infusion vs. intermittent injection of antidepressant) in large brain areas. However, the results do not deny possibility of changes in discrete areas, which were not studied in the current study applying PET.

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Antidepressant-Induced Increase in High-Affinity Rolipram Binding Sites in Rat Brain: Dependence on Noradrenergic and Serotonergic Function

Abstract: The effects of antidepressant treatment on the high-and lowaffinity rolipram binding sites on type 4 phosphodiesterase (PDE4) were determined; previous work had shown that repeated antidepressant treatment increases the overall expression of PDE4.

Cited by 32 publications

References 32 publications

Conversion of Phosphodiesterase-5 (PDE5) Catalytic Site to Higher Affinity by PDE5 Inhibitors

Conversion of Phosphodiesterase-5 (PDE5) Catalytic Site to Higher Affinity by PDE5 Inhibitors

Effects of Repeated Treatment with Phosphodiesterase-4 Inhibitors on cAMP Signaling, Hippocampal Cell Proliferation, and Behavior in the Forced-Swim Test

In vivo and in vitro measurement of brain phosphodiesterase 4 in rats after antidepressant administration

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