Antidepressant-induced increase in high-affinity rolipram binding sites in rat brain: dependence on noradrenergic and serotonergic function.
The effects of antidepressant treatment on the high- and low-affinity rolipram binding sites on type 4 phosphodiesterase (PDE4) were determined; previous work had shown that repeated antidepressant treatment increases the overall expression of PDE4. Rats were administered different doses of the antidepressant drugs desipramine or fluoxetine, or saline, for 1, 7, or 14 days. [3H]Rolipram and [3H]piclamilast were used to assess the high-affinity rolipram binding sites (HARBS) and low-affinity rolipram binding sites (LARBS) on PDE4 in the hippocampus and cerebral cortex. Repeated, but not acute, treatment with the antidepressants increased [3H]rolipram binding to membrane fractions in a dose-dependent manner; the HARBS component of [3H]piclamilast binding also was increased by these treatments. By contrast, the LARBS component of [3H]piclamilast binding was not altered. [3H]Rolipram and [3H]piclamilast binding to the cytosolic fractions of rat cerebral cortex and hippocampus was not altered by the antidepressant treatments. 6-Hydroxydopamine (6-OHDA; 300 microg i.c.v.) and 5,7-dihydroxytryptamine (5,7-DHT; 200 microg i.c.v.) were used to lesion noradrenergic and serotonergic neurons, respectively. The effects of desipramine, but not fluoxetine, on [3H]rolipram and [3H]piclamilast binding to rat hippocampal membranes were blocked by the 6-OHDA-induced lesion. By contrast, the effects of fluoxetine, but not desipramine, were reduced by the 5,7-DHT-induced lesion. This indicates that the up-regulation of the HARBS by desipramine and fluoxetine requires the integrity of noradrenergic and serotonergic neurons, respectively. Collectively, these results suggest that antidepressants, although acting through different pathways, may eventually lead to the regulation of components of the cAMP signal transduction system.
Zhao
Yu
Y
Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Zhang
Han-Ting
HT
O'Donnell
James M
JM
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D001665:Binding Sites; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011941:Receptors, Adrenergic / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D020889:Rolipram / Q000494:pharmacology*; D013997:Time Factors; D014316:Tritium
D000928:Antidepressive Agents; D001549:Benzamides; D011725:Pyridines; D011941:Receptors, Adrenergic; D011985:Receptors, Serotonin; D014316:Tritium; D020889:Rolipram; D003891:Desipramine; C087566:piclamilast